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Herbs

Oregano

Glossary, HerbsSuccess Chemistry Staff
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Oregano

is a close relative of the marjoram and applies as this also as a medicinal plant. With its mild-spicy taste, oregano plays an important role in the Mediterranean cuisine. Classically, this herb is found on pizza and in tomato sauce. But it also has a lot of other uses. Oregano blends well with fruity tomatoes, cucumbers, and salads. Also with egg dishes, sauces, potato, and tomato soup, this aromatic herb fits.

Oregano as a medicinal herb

Although oregano is usually known only as a kitchen herb, it finds in the folk medicine relatively much attention. Oregano can be used for a variety of ailments due to its containing ingredients.

Oregano was already known in antiquity and the Middle Ages as a herb with great healing power. Oregano was used to treat painful hemorrhoids. In gynecology, the medicinal herb was used to initiate the birth. Furthermore, oregano was in the Middle Ages as a tried and tested means to shield themselves from demons, witches and the devil. From oregano lentils in the house and incense with oregano promised the same effect as garlic used against vampires.

In old herbal books, oregano, as well as some oregano species commonly referred to as Wohlgemuth (Wolgemut) or Dosten. In the herbal book by Petri Andreae Matthioli, the herb was used for both internal and external applications. Oregano was recommended among other things with itching (application: Oreganobad), with tumors of the almonds (presumably almond inflammation) or with the Wundbehandlung. Oregano has also been used to treat gastrointestinal complaints, coughing or tracheal diseases. The herb was usually mixed with red wine or drunk as pressed juice.

Today, however, oregano is used for problems in the gastrointestinal tract. The tannins and bitter substances in the oregano have an anticonvulsant effect, thus helping with gastric and/or intestinal cramps as well as flatulence and casually stimulate the appetite.

The plant parts of the oregano, especially the leaves and the herb contain a variety of different active ingredients. The containing essential oils, tannins, and bitter substances have the following healing effect:

  • antibacterial

    1. carminative

    2. appetizing

    3. cough expectorant

    4. antifungal

    5. antioxidant

To relieve stomach and intestinal complaints or chronic bronchitis, oregano is usually taken in the form of tea. One teaspoon of dried cabbage or two teaspoons of fresh oregano is poured over with 250 to 300 ml of boiling water. The infusion is left covered for about 10 minutes and then drunk. Even with a bacterial cough and infestation of Candida fungi, Oreganotee can be drunk supportive.

externally, oregano is used in inflammatory skin problems, as the ingredients in the essential oil of oregano (especially phenols and carvacrol) are classified as antibacterial and anti-inflammatory. Oily ginger tinctures are used to treat greasy, blemished skin, which is used to dab the affected areas of the skin.

Oregano - Medicinal herb of the Mediterranean

Oregano is an indispensable part of the Mediterranean cuisine. In the West, it is almost exclusively associated with delicious dishes from Italian cuisine.

Oregano is not only used as a medicinal but also as a spice plant.

But also the people of the eastern Mediterranean know and love oregano. For example, anyone traveling to Turkey will come across this tasty herb again and again; as well as in Greece and Spain. Incidentally, in the Middle Ages, it was often used there for dyeing, for example, wool. But back to the present and to Italy, where Oregano has also been known for centuries and is prized for its unmistakable flavor. Pasta sauces are mainly prepared here. But also with lamb dishes and everything that has anything to do with tomatoes, oregano is often used for seasoning. In addition, it is indispensable for a real Italian pizza.

Where does oregano come from?

Oregano is not only widespread in the Mediterranean, but the herb also has its original home here. It belongs botanically to the family Lamiaceae. In Germany, oregano is also known by names such as "wild marjoram", "Dost", "Dorst" and "Wohlgemuth". The latter points to the healing properties associated with the condiment. It helps the digestive tract to the legs and relieves coughing. For a soothing tea, add one teaspoon of dried oregano to a one-quarter liter of boiling water and infuse for five minutes.

How is oregano used?

Herbs are very important in Italian cuisine. Without basil, parsley, sage, and oregano, Italian dishes are almost unthinkable. They are mainly used fresh in salads, in sauces for pasta dishes, for egg dishes and in the context of tomatoes. A classic example is "Insalata Caprese"; an appetizer consisting of tomatoes, mozzarella, and fresh basil. Oregano is often used in a dried form for meat dishes. Classically, the Italian mom will use it in lamb dishes; Oregano also goes well with pork and beef.

When is oregano available and what should you pay attention to when buying?

Oregano is grown today almost everywhere in the world and is therefore available all year round fresh in the supermarket, in the vegetable trade and at weekly markets. It is usually offered in pots. In addition, the herbs are also dried and rubbed. It then has a slightly changed, woody and intense taste. In fresh plants, make sure that the leaves do not hang limp and have no brown edge.

Grow oregano yourself

As long as you have a sunny spot in the garden, this spice herb can easily be grown by yourself. You can sow just as well as-as of May - buy also bought young plants. Those who prefer seeds should only lightly press the earth over them. Oregano is a so-called "light germ," so the seeds should not be buried too deep in the ground. Moderate, but regularly poured, there will soon be a rich harvest. Partly dry part of it for the winter months.

 

 

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Sage

Herbs, GlossarySuccess Chemistry Staff

Sage medicinal benefits 

With over 60 ingredients, sage combines the healing properties of eucalyptus, rosemary, wormwood & tea tree oil.. It is a popular Mediterranean herb and is known for its use in saltimbocca or entrecote. Sage is ideal for refining meat dishes of all kinds and pasta. If the aroma is too intense, you can fall back on the much milder young leaves. The healing effects of sage can be used, for example, in homemade cough syrup, sage cough sweets or tooth-care throat drops.

The true sage - Latin name Salvia officinalis - is considered with its disinfecting and astringent effect as one of the most important medicinal herbs and played a major role in ancient and Celtic mythology. The Egyptians also appreciated him very much. They gave their women sage juice to promote fertility. Perhaps the following advice comes from this: women should eat a raw sage leaf every time they walk the garden. Sage leaves are also an integral part of ancient medicine, the ancient Ayurveda. In the Middle Ages, the herb was considered a panacea and was mainly grown in monastery gardens.

Pharmacists and doctors at that time appreciated him especially as a wound treatment for wound cleansing and hemostasis. Already in the 6th-century monks brought the medicinal plant across the Alps in northern regions. Therefore, it is not surprising that at early mention the plant appears in the monastery plan of St. Gallen, the monk Strabo from the monastery Reichenau and Hildegard von Bingen. The herbal boom in the 1980s made sure that the forgotten herb gardens were recreated in many monasteries and opened to the public. Even in cottage gardens, Salvia officinalis is a traditional plant that must not be missed. Today, more and more people trust in herbal medicine, and so the herb finds application in many complaints. As a spice herb,

Origin of sage

The home of sage is the Mediterranean. But now you can find this herb and spice herb in many gardens, where it prefers a heat-loving plant full sun and light soil. He does not love waterlogging and too much fertilizer, on the other hand, he withstands drying times very well. As a heat-loving plant, however, it needs a winter shelter in rough locations, for example, brushwood. Wild it still grows in Italy, mainly on the Adriatic coast in sandy and calcareous areas. In addition to Salvia officinalis, there are numerous other species of sage, which are cultivated partly in the garden as ornamental plants. All sorts of sage belong to the family of the mint family and bloom in different colors. The true shows from May to July its approximately two inches long blue to purple flowers, which make an excellent bee pasture. The perennial, bushy plant grows up to 80 cm high and lightens easily if you do not prune it back after flowering. Striking are the elongated silvery-green and slightly felty leaves. They emanate an aromatic fragrance through the contained essential oils. The leaves also contain the manifold healing powers.

Special features of sage

Sage leaves have a sharp, dry and strong, slightly bitter taste. In the kitchen, they are therefore particularly suitable for high-fat meals. However, mainly sage is used as a medicinal herb. Its known active ingredients are essential oils that include thujone, borneol, cineole, and camphene among other things, the leaves are rich in tannins and bitter substances, terpenes and numerous flavonoids. For the bitter substances, it is above all the typical salvin. The amount and composition of these substances are highly dependent on climatic conditions and the harvest time, which is most ideal before flowering. Together, the ingredients have antibacterial, antiviral, fungicidal, astringent and antiseptic properties. Thujone is poisonous, therefore you should not consume sage tea or drops for a long time. The name Salvia comes from Latin and means salvation or healing. This says a lot about the broad effect of the plant. The medicinal herb is used for tea, tincture, drops, sage oil, sage wine, and powder; in the industry for throat sweets and pastilles. For the applications mainly the dried sage leaves are taken. To do this, cut off some stems before blooming, hang them up in tufts or lay them out to dry in layers not too thick in the shade. In the oven or in the Dehydrator you can also dry at a maximum of 40 degrees. After drying keep dark and cool. You can also buy dried sage leaves. Pay attention to the quality.

Sage as a medicinal herb - earlier and today

In natural medicine, the use of medicinal herbs has a long tradition. Even Hippocrates, Hildegard von Bingen, and Paracelsus - to name just the best known - recommended the use of sage in fever, colic, urinary tract disorders, loss of appetite, colds, dental disease and red dysentery. During the various plague epidemics, the herb also played a significant role. Thieves rubbed their bodies with a mixture of sage leaves, lavender, rosemary, and thyme to protect them against the pest and were able to plunder the houses of the dead without becoming infected. The medicinal herb was also used for cramps, itching, pneumonia, somnolence, digestive problems, and body aches. Old recipes recommend sage powder or fresh leaves for teeth and gums for cleansing and strengthening. As early as the 10th century, Arab doctors, scholars, and philosophers used sage tea with honey to enhance their mental abilities. As an essential sage oil, it has a disinfecting and antispasmodic effect. In addition, the oil is suitable for colds for inhalation. Due to the disinfecting effect sage leaves were burned for a long time as fumigants in the room of the seriously ill.

Even today, many of these recommendations are valid and medical research can largely confirm this ancient knowledge. The active ingredients actually provide relief from everyday problems. Naturally, the herb is used today in:

  • Gingival and oral mucosal inflammations

  • Colds and sore throat

  • Tonsillitis, pharynx, and laryngitis

  • heavy sweating

  • for wound healing

  • mild indigestion

  • bronchitis

  • Panting and smoker cough

  • rheumatism

  • headaches

  • Nervousness and weak nerves

  • for breastfeeding during lactation

  • thin, graying hair

  • skin problems

The best-known uses of sage are certainly inflammation in the mouth and throat and various dental diseases. For this, rinsing or gargling with sage tea or mouthwash is recommended. Even special ready-made salvia preparations can help with these complaints. Because sage has anti-inflammatory and antispasmodic properties, it is also often included in toothpaste and cough sweets. Known is the effect of sage tea in case of excessive sweating, especially during menopause. Sole tea is also helpful for girls during puberty and for women in menstrual disorders. Responsible for this are probably the contained tannins and terpenes.

Regular drinking of cold tea - 2-3 cups a day, but not more than four weeks, then take a break - inhibits sweat production. The tea can bring relief for indigestion. These include the irritable stomach syndrome, which can cause flatulence, cramps, pain, and loss of appetite. It is even believed, according to recent studies, that sage tea has an effect on the lowering of blood sugar levels. This would be ideal for diabetics. The antibacterial and anti-inflammatory effect of sage is ideal for wound healing and for bad and oily skin. Salvia bites from a strong decoction are recommended here. They have a calming, astringent and anti-inflammatory effect. In lactating women, sage tea prevents milk flow and should therefore not be consumed during breastfeeding. In the case of weaning, however, it can be helpful. Thin and graying hair regularly flushed with a strong broth, makes the hair stronger and gives it a nice dark color.

Even with greasy hair helps a flush with the broth. Seating baths with salvia or the daily intake of sage wine to support the nervous system, such as stress and excitement. The herb calms and brings serenity, at the same time it also stimulates and strengthens the circulation. In studies, even an anticarcinogenic effect of sage was found. The contained diterpenes are said to trigger the cell death of the tumor cells. Leukemia and lymph node cancers are being discussed. Like the Egyptians, the Englishman John Gerard found in the Middle Ages: "Sage is uniquely good for the head and brain and accelerates the nerves and the memory". A team from the Newcastle up Tyne Medical Plant Research Center did a study on this and the result confirmed this statement by Gerard.

The reason is an enzyme of sage, which inhibits the degradation of the messenger acetylcholine. In Alzheimer's disease, this messenger substance is broken down in the brain. It is now being researched which ingredients of sage are responsible for this and whether a drug can be developed from them. Studies have also observed the inhibitory effect on the herpes virus. Ritual fumigation with the purifying effect of medicinal herbs has always existed. Today, these fumigations are again increasingly carried out, for example, for cleaning rooms at home, after illnesses, significant changes in life or in agriculture, the stables.

How can you apply sage 

Applied internally, tea is the simplest remedy. It strengthens the resistance of the organism and the nervous system. Ideal for menopausal symptoms with palpitations, blood rush in the head and sweating. Add 2 teaspoons of dried sage leaves and bake with 1/4 l of boiling water. Let it rest for 10 minutes, strain. Depending on your taste you can add some honey or a splash of lemon juice. In case of sweating and indigestion drink cold.

A weekly sitz bath can contribute to mental health. Women also help a sitz bath in case of discharge or soreness in the genital area. For this, let 4 handfuls of dried sage leaves in about three liters of cold water overnight. Heat to boiling the next day, strain and place in the bath water (38-40 degrees). Bathing in it for 20 minutes. Sage wine can also strengthen the nerves. Add 80 g of dried sage leaves and strain for 10 days in 1 liter of sweet wine. Then drain through a cloth. Take 1 tablespoon after each meal.

The sage tincture is like tea against perspiration, diarrhea, and stomach upset. For this, 50 g of dried sage leaves are mixed with 1/2 liter of 50% alcohol in a bottle. Close and allow to shake for 10 days, shaking frequently. Then drain through a cloth and fill in a brown pharmacy bottle - possibly with a pipette. Take 30 drops of tincture 3 times a day for 1 tablespoon of water.

Sage envelopes can help with spotty skin. The herb regulates sebum production and fights bacteria. The envelopes can also help with wound healing. Add 2 tablespoons of dried sage leaves to 150 ml of boiling water, infuse for 20 minutes, strain. Soak a clean cotton cloth in the warm infusion, gently wring it out and place it on the wound. Envelopes can also be applied to the face for blemished facial skin or cotton swabs placed in the appropriate places. Leave for 20 minutes, then rinse with lukewarm water.

Ointment water helps with bleeding gums, it heals and strengthens the gums. To chop 6 fresh sage leaves small. Bring 1/2 liter of water and a pinch of salt to a boil and infuse the sage leaves. Allow to cool, pour through a fine sieve and squeeze the leaves well. After brushing, use as gargle water.

For gingivitis, chewing fresh sage leaves or rubbing in and rubbing with leafy pulp is recommended. Fresh sage leaves are also said to help with bad breath. For pressure points of dentures or braces repeated rubbing with fresh leaves can help.

The homemade sage syrup also helps with colds and is also taken by older children. To do this, boil 1 kg of sugar in 1 liter of water. Then add 4 handfuls of fresh sage leaves and 2 sliced bigotries. Run for two days in a cool place, strain and boil briefly again. Bottling hot and sealing well. For cold and sore throat, drink 1 tablespoon of syrup 3 times a day on 1 glass of warm water.

Beware of side effects!

In principle, internal applications with sage tea, tincture or oil should only be carried out for the duration of the symptoms. The active ingredient thujone can cause symptoms of intoxication if it is taken longer and in larger quantities. Signs of toxic effects include accelerated heartbeat, convulsions, nausea, dizziness and heat. External applications and use as spice are generally harmless. For pregnant women, infants and nursing mothers, the medicinal herb is in no form. Suckling tea, on the other hand, is a popular remedy for reducing milk flow. Allergic reactions occur sporadically.

lavender

Glossary, HerbsSuccess Chemistry Staff

lavender 

Lavender (Lavandula angustifolia) - Characteristics, cultivation, use, and healing properties

The purple flowers of lavender give the herb bed an unmistakable splash of color and its wonderful scent enchants everyone's senses. Lavender is an integral part of French cuisine and can be found in every herb-of-Provence mixture. Because of its particularly intense aroma, it is advisable to dose lavender very sparingly. The herb is good for flavoring meat dishes, but also desserts, jams, and drinks get a unique touch with a touch of lavender. The flowers can also be used for salads and dips.

Origin and occurrence of lavender

The real lavender is a classic Mediterranean plant, which occurs wild mainly in the countries of the Mediterranean, including Greece, southern France, and Italy. It can be found there especially in dry, barren and sun-drenched altitudes in regions with calcareous soils. A region of lavender that is very attractive to tourists is French Provence, where lavender fields are very common.

Due to its great popularity, lavender has been introduced and cultivated in many countries. Significant cultural occurrences of lavender can be found next to France in England, Morocco and the United States.

Real lavender

The true lavender (Lavandula angustifolia, sometimes also Lavandula officinalis) is a member of the labiate (Lamiaceae). It is also part of the botanical subfamily Nepetoidaea, which includes many other well-known herbs such as rosemary, sage, savory or peppermint .

The genus of lavender plants (Lavandula) includes more than 30 different types of lavender . In addition to the real lavender, lavender lavender (Lavandula stoechas), broadleaf lavender (Lavandula latifolia) and French lavender (Lavandula dentata) are well-known representatives of this genus.

Characteristics of lavender

In the botanical sense, lavender is a perennial subshrub that can reach heights of growth of up to 140 cm. Most of the plants in this country, however, achieve much lower stature heights of 40 to 70 cm. Lavender forms elastic, stable and relatively short roots.

Lavender leaves are quite distinctive and easy to recognize. They usually have a light green to greyish green color. The lanceolate, ganzrandigen and elongated leaves are up to 5 cm long and are on both sides of the leaves with a white felt (leaf hair) occupied. The leaves of the lavender sit on the ascending and upright branches on which they are arranged opposite. The branches are usually heavily branched. As you grow older, the leaves turn greener.

The real lavender usually flowers between late May to mid-September . There it forms striking violet, rarely white flowers, which are arranged in so-called Scheinquirlen. These in turn form false notes, in which the lip-shaped flowers sit. Each flower consists of four stamens, a two-part upper and three-part lower lip and a four-part ovary. After the flowering period, at the time of fruit ripeness, small brownish nut fruits are formed.

Real lavender - sowing and care

Although it is usually easier to transplant finished lavender plants from the hardware store or garden center in the garden or on the balcony, it can sometimes be more sustainable to grow the lavender from your own seeds. Many purchased plants are sometimes overfertilized, so they survive only one season.

Who wants to sow lavender, should know how the natural habitat of the plant is. It thrives magnificently on sun-exposed slopes, with calcareous, well-drained and nutrient-poor soils. It is therefore recommended not to cultivate the lavender pure in commercially available potting soil or in clayey or clayey garden soils. If no optimal substrates are available, the soil or the soil should be mixed with aggregates such as pumice, lava or zeolite.

The sowing succeeds best in Vorkultur on the window sill or in a room greenhouse. Since germ temperatures around 20 ° C are required, the lavender seeds should also have a correspondingly warm environment. Ideally, the pre-culture should take place between the end of February and the end of March, in order to transplant the young plants into the field or on the balcony. Germination requires some patience. Germination can take up to four weeks. It may be advantageous to use a mineral growing substrate for sowing. A 50:50 mixture of vermiculite and perlite appears optimal. Always keep the seed soil moist, but not too humid.

sowing in the field is also possible, though a bit more difficult. Here it should be ensured that no more night frosts occur. The seeds can be easily pressed into the ground at a distance of about 30 x 30 cm. Since the lavender is a light germ, the grains should be incorporated only about 0.5 cm deep into the soil. The best time for sowing outdoors are the months of April and until the end of May.

Fertilization: Lavender is used to nutrient-poor locations and therefore does not need a lush supply of fertilizers . It is usually sufficient to provide the plants once a year with compost or light NPK fertilizer. If you have plants in tubs or smaller pots, you may need to fertilize a little more often.

Water supply: The herb needs only a little water. Therefore, should only be poured when the soil or the soil is almost dried out. The plant will cope without any problems for a while without water. Significantly more harmful is an oversupply of water. Too much water can promote root rot and other diseases.

Overwinter: Lavender is considered frost tolerant, ie the plant can survive short periods of freezing. If you want to let the plant hibernate outdoors, you should take some measures. The cover appears optimally with very coarse mulch material, straw as well as twigs and foliage. The latter protects against dehydration. Without cover, the water freezes in the near-surface soil layers, so that the lavender can no longer absorb water. It is important that the lavender branches should be cut back already in late summer, otherwise frostbite may occur. Lavender plants that are in pots can be stored in the garage or in the basement in unheated but frost-free areas (see Making herbs winter proof ).

Lavender and its uses

The lavender is not only a popular ornamental plant, it is also a very versatile herb. As a fragrance, it is used in numerous cosmetic products. As a culinary herb lavender lends a spicy touch to many Mediterranean dishes and as a medicinal herb it can sometimes cause minor miracles.

Lavender in the kitchen

Lavender is considered an excellent culinary herb that can be used for numerous recipes. The flowers, the leaves as well as entire branches are used. Care should always be taken to use the real lavender (Lavandula angustifolia) and not the shaggy lavender. The real lavender has a distinctive spicy and camphor-like flavor, which is sometimes flowery and slightly bitter.

Fresh lavender branches, for example, flavor meat dishes of all kinds . Chicken, lamb and fish dishes have an excellent taste when lavender is combined with thyme or rosemary.

Chased or chopped lavender leaves provide a refined taste in many cheeses such as goat cheese, soft cheese, gorgonzola or raclette cheese with lavender. The aroma of lavender is also suitable for hearty creamy soups. In principle, the dosage should always be handled very sparingly, since the leaves are usually very aromatic and produce an intense taste.

Lavender flowers are often used for sweets. For example, fruit juices that receive berry fruit can develop a very excellent aroma when mixed with a few lavender flowers. Lavender is also very suitable for cakes (eg Guglhupf), truffles and ice cream.

A special feature is lavender honey , which tastes lovely and has a fine floral aroma. For high-quality honeys the lavender taste is fine. Lavender honey is also considered very healthy due to its many minerals.

Gerebelter lavender leaves are occasionally contained in herbal mixtures such as herbs of Provence. However, the herb is not an ingredient in the original French herbal blend . Although lavender is listed as an ingredient in many sources, this seems to be more of a German peculiarity, mixing herbs from Provence with lavender.

Lavender as a medicinal herb

The true lavender looks as a medicinal herb on a long and impressive history. The Romans, Egyptians and Greeks considered the lavender to be an almost sacred herb. In the Roman military, the plant was used as a wound healing and stimulant, among other things. Both Greeks and Romans used lavender as an ingredient for their bathwater. The Roman physician Dioskurides has already reported in detail in his book Materia Medica (1st century AD) about the lavender and its applications.

The herb and its healing properties were also known in European countries, so that it was cultivated in many monastery gardens and was also used in many diseases and complaints. Hildegard von Bingen described the lavender as a warm and dry herb, which was administered by her among other things in lung and liver diseases as well as in psychological conditions. Paracelsus already knew its calming effect and used the herb as a sedative and for the treatment of heart and digestive complaints.

The medicinal herb is mentioned in almost all medieval herbal books . In the herbal book by Pietro Andrea Matthioli (late 16th century) numerous internal and external applications have been described. For example, lavender has been used to treat paralysis, cramps, stomach disorders as well as liver and spleen disorders. There it was recommended to boil the lavender in wine or water (tea) and to drink it or to spread it on the arteries as schnapps (distilled water).

In addition, the lavender was recommended for various dental diseases, language problems and body aches. He was also given to pregnant women who have contractions. In the latter, pure lavender branches were placed on the stomach.

 

Today, lavender is mainly used for nervous restlessness, mild depression, insomnia and as a mild sedative. The sleep-inducing, sedative and muscle-relaxing effects of lavender have been confirmed in many scientific studies. Responsible for the calming, sedative effects are certain essential oils in lavender, vader fabric linalool .

In addition to the sedative effect of the ingredients of the lavender also have antibacterial (including Shigella, Staphylococcus aureus, Escherichia coli), antifungal, chiral and anticonvulsant [1]. For the antibacterial and antifungal properties, especially the essential oils are responsible. Depending on the variety and growing area of more than 40 essential oils may occur. The cholagogue properties are mainly caused by the containing tannins.

Lavender is used in natural medicine today as it was then as a tea or as a bath additive. Other dosage forms include aromatherapy with essential oils or the use of lavender pillows.

Preparation of lavender tea

For the preparation of 250 ml of lavender tea, cover a spoonful of lavender leaves or flowers with 250 ml of boiling water. The tea should last at least 7 minutes, but not longer than 10 minutes. The tea should not be sweetened if possible.

Lavender tea can be drunk in nervous restlessness, insomnia and minor stomach and intestinal complaints such as bloating or diarrhea.

To prepare a herbal bath with lavender, pour about 40 to 50 grams of lavender flowers with one liter of boiling water in a container and leave for about 15 minutes. The container can then be poured into the prefilled tub. Even if the lavender bath is quite relaxing and soothing, the bath should be stopped after 25 minutes at the latest.

Some ingredients of lavender may also help in the treatment of so-called Hodgin lymphoma. Under laboratory conditions, lymphoma cells could be inhibited in their growth (proliferation).

Another medical research approach is the use of lavender extracts in Alzheimer's disease. For example, learning deficits in Alzheimer's patients could be reduced, or the enzyme acetylcholinesterase, which plays a role in the onset and progression of the disease, can be sustainably inhibited.

Buying lavender - here is what to pay attention to

Lavender is available in all imaginable shapes today. Fresh lavender plants can usually be bought in early summer in supermarkets, hardware stores and garden centers. If you want to buy the lavender as a useful plant, you should pay attention to the botanical name (Lavendula angustifolia). Sometimes also the Schopflavendel comes into the trade, which looks very similar to the real lavender.

It should also be ensured that the leaves do not hang, the soil is not too wet and that the ratio plant height to pot size fits. A lavender plant that is three times as high as the pot should not be purchased if possible.

Dried lavender leaves and flowers, which are used for teas, recipes and herbal baths, are available from many herbalists, sometimes in larger supermarkets or in numerous online shops. Again, the botanical name should be checked. The herbs should be packed aroma-tight and spread when opening a strong lavender-scented aroma. Lavender flowers are usually much more expensive than lavender leaves.

For aromatherapy, scented candles, lavender soaps or lavender bath also finished lavender oil can be purchased. If you want to use lavender oil for aromatheurotherapeutic purposes, you should be careful to get real lavender oil. There are many synthetic products available on the market, but they are not suitable for this purpose.

Astragalus

Herbs, GlossarySuccess Chemistry Staff

INTRODUCTION

Astragalus root (Astragalus membranaceus and Astragalus

mongholicus) (Figs. 1 and 2; flowers are shown in Fig.

2) is one of the most important plant products used

in traditional Chinese medicine (TCM) for supporting

immune resistance ( ; wei qi) and energy production

( ; bu qi). Astragalus is also one of the most popular

ingredients in botanical dietary supplements for its

putative effect of supporting healthy immune function.

Despite the widespread use of this botanical among

TCM practitioners and its extensive use in botanical

supplements, there are few clinical trials supporting

its use, though those that are available are positive.

Numerous preclinical studies provide evidence for a

number of pharmacological effects that are consistent

with the traditional and modern use of astragalus.

BACKGROUND

Traditional and Modern Uses

In Asia, astragalus is commonly used according to both

its traditional Chinese medical indications as a general

tonifier and specifically for immune enhancement and for

modern biomedical indications such as immune, liver, and

cardiovascular support. It has been used for the prevention

of the common cold and upper respiratory tract infections

and is widely prescribed to children for prevention

of infectious disease, though formal clinical English language

studies regarding this use are lacking. In the West,

astragalus is primarily used as an immune modulator.

Astragalus potentiates recombinant interleukin-2 (rIL-2)

and recombinant interferon-1 and -2 (rIFN-1 and -2) immunotherapy

and by lowering the therapeutic thresholds,

may reduce the side effects normally associated with these

therapies. The data and opinion of those expert with the

use of the botanical suggest that astragalus is useful as a

complementary treatment during chemotherapy and radiation

therapy and in immune deficiency syndromes. There

is some modern evidence for its use in hepatitis and the

treatment of cardiovascular disease.

In TCM and Western clinical herbal medicine, astragalus

is most commonly used in combination with other

botanicals and is very seldom used as a single agent. There

are numerous studies of some of the classic combinations

of astragalus (e.g., astragalus and Angelica sinensis). These

have not been reviewed, but use of formulas is more consistent

with the use of the astragalus than with the use of

the herb alone according to traditional Chinese medical

principles.

CHEMISTRY AND PREPARATION OF PRODUCTS

The primary compounds of interest in astragalus are triterpenes,

polysaccharides, and flavonoids. The triterpene astragaloside

IV is a relatively unique marker for astragalus

species used in Chinese medicine. A variety of preparations

are utilized in clinical practice and in herbal supplements.

A number of preparations, including crude extracts,

isolated polysaccharides, and triterpene saponins,

have been subject to study and correlated with activity.

Clinically, in China and among some practitioners in the

United States, decoctions are frequently given. However,

due to the time required for cooking and the subsequent

smell and taste of Chinese herb preparations in general

(though astragalus is very agreeable), many consumers

and practitioners prefer crude powder or extract preparations

(capsules, tablets), freeze-dried granules, or liquid

extracts. Astragalus is also used as a relatively common

ingredient in soups, especially during winter months.

Polysaccharides (12–36 kD) have been most often

correlated with immune activity, while triterpene

saponins have been predominantly associated with cardiovascular

and hepatoprotective effects. Astragalus

polysaccharides are generally composed of a mixture of

D-glucose, D-galactose, and L-arabinose or D-glucose

alone. The glucose units appear to be primarily -(1,4)-

linked with periodic -(1,6)-linked branches (1,2). The

triterpene glycosides vary by position, number, and type

of sugar residues at positions 3, 6, and 25. Several of

these “astragalosides” (e.g., astragaloside IV; Fig. 3) are

composed of a single xylopyranosyl substituent at the 3-

position, which may or may not be acetylated. Others possess

either disaccharide or trisaccharide substituents (3–

5). Primary flavonoids of astragalus for which activity has

been reported include calycosin, formononetin (Fig. 3),

and daidzein (Fig. 3) and additionally include isorhamnetin,

kaempferol, and quercetin, among others (6).

PRECLINICAL STUDIES

Pharmacokinetics

Pharmacokinetic data available in English language publications

on astragalus, its crude extracts, or its constituents

are very limited. In the most detailed study to

date, the pharmacokinetics of a decoction of astragalus,

the preparation most used traditionally were investigated

in four models: four complement in silico, a cacao-2 intestinal

cell model, an animal, and a human volunteer

(n = 1). Intestinal absorption was demonstrated for several

flavonoids including calycosin and formononetin,

along with their aglycone metabolites in all four

models. Triterpene saponins, used as chemical markers

of astragalus (e.g., astragaloside I and IV) in the Pharmacopoeia

of the People’s Republic of China and the American

Herbal Pharmacopoeia, were lacking, likely due to

their low concentrations in the preparation. In the human

volunteer, nine flavonoids, including calycosin, formononetin,

and the isoflavone daidzein, were detected

Figure 2 Astragalus flowers. Source: Photo courtesy of Bill Brevoort, American

Herbal Pharmacopoeia.

in urine (7). In animal models (rats and dogs), astragaloside

IV, which has demonstrated cardioprotective activity,

showed moderate-to-fast elimination. The half-life in male

rats was from 67.2 to 98.1 minutes, in female rats 34.0 to

131.6 minutes, and was linear at the intravenous doses

given. The highest concentration of astragaloside IV was

found in the lungs and liver. Only 50% of the compound

was detected in urine and feces. Binding to plasma protein

was also linear at the concentration of 250–1000 ng/mL.

Slow systemic clearance of astragaloside IV occurred via

the liver at approximately 0.004 L/kg/min (8).

In another pharmacokinetic study, a two compartment,

first-order pharmacokinetic model was

used to describe the pharmacokinetics of intravenously administered

astragaloside IV. Systemic clearance of this

triterpene was reported as moderate and distribution into

peripheral tissues was limited (9).

Pharmacodynamics

A large percentage of research on astragalus has focused

on its immunostimulatory activity and its purported

ability to restore the activity of a suppressed immune

system. More recently, interest in its potential as a cardioprotective

agent has been shown. Reviews of a limited

number of clinical trials and preclinical data provide some

evidence for its usefulness in the prevention of the common

cold and as an adjunct to cancer therapies. There is

limited evidence to suggest a benefit to the cardiovascular

Astragalus 31

  • O

  • O

  • O

  • OH

  • OH

  • HO

  • O

  • H

  • OH

  • O

  • OH

  • OH

  • HO

  • OH

  • HO

  • O

  • O

  • OCH3

  • HO

  • O

  • OH

  • O

  • HO

  • Astragaloside IV

  • Formononetin

  • Daidzein

Figure 3 Some major constituents of Astragalus.

system, with improvement in clinical parameters associated

with angina, congestive heart failure, and acute myocardial

infarct. There is also some indication from animal

studies supporting its use in the treatment of hepatitis and

diabetes.

Immunomodulatory Effects

There are relatively strong preclinical data of pharmacological

mechanisms that provide support for the putative

immunomodulatory effects of astragalus.

Cancer

In a rat study, animals were pretreated orally for 50 days

with a low or high dose of astragalus extract (3.3 or

10 g/kg/day) prior to IP injection of doxorubicin (cumulative

dose of 12 mg/kg over a 2-week period). After 5 weeks

of the final injection of doxorubicin, a significant inhibition

of cardiac diastolic function was observed. This was

accompanied by ascites, catexia, decreased heart weight,

and increased mortality. Treatment with astragalus at both

doses significantly attenuated the negative effects of doxorubicin

on cardiac functions and ascites, while the high

dose also improved survival. This protective effective

was at least partially associated with the ability of astragalus

to attenuate changes in cardiac SERCA2a mRNA

expression (10).

A broad array of immunomodulatory effects has

been demonstrated in numerous preclinical studies that

suggest a substantial value of astragalus in conjunction

with conventional cancer therapies. The most relevant

of these was a series of investigations conducted

by researchers at the MD Anderson Cancer Center

that found that astragalus extract restored to normal

the immune response of patients’ mononuclear cells

that were grafted into rats immunocompromised by cyclophosphamide.

These researchers concluded that astragalus

and its polysaccharide fraction reversed the immunosuppressive

effect of cyclophosphamide (11–15). In

other studies, astragalus and its various fractions were

shown to stimulate macrophage phagocytosis (16) and

hematopoiesis (17).

One study reported on the gastroprotective effects

of astragalus extract (characterization not reported) in human

peritoneal mesothelial cells (HPMCs) subjected to

gastric cancer cell lines. Upon incubation with cancer cell

lines, apoptosis of the HPMC cells was observed. The astragalus

preparation, via regulation of Bcl-2 and Bax, partially

inhibited apoptosis. The authors interpreted these

findings as a potential that astragalus may slow down the

metastasis of the primary cancer and is therefore a potential

treatment for gastric cancer (18).

The ability of an astragalus fraction to potentiate the

effects of rIL-2 has been demonstrated in in vitro assays.

Lymphokine-activated killer (LAK) cells were treated with

a combination of the astragalus fraction and 100 units/mL

of IL-2. The combination therapy produced the same

amount of tumor-cell-killing activity as that generated

by 1000 units/mL of rIL-2 on its own, thus suggesting

that the astragalus fraction elicited a 10-fold potentiation

of rIL-2 in this in vitro model (19). These findings were

confirmed in a follow-up study by the MD Anderson researchers

using LAK cells from cancer and AIDS patients.

In this study, the cytotoxicity of a lower dose of 50 g/mL

of rIL-2 given with the astragalus fraction was comparable

to that of a higher dose of 500 g/mL of rIL-2 alone

against the Hs294t melanoma cell line of LAK cells. With

the combination, the effector-target cell ratio could be reduced

to one-half to obtain a level of cytotoxicity that was

equivalent to the use of rIL-2 alone. In addition, the astragalus

fraction was shown to increase the responsiveness

of peripheral blood lymphocytes that were not affected by

rIL-2. In this study, and in another by the same researchers,

it was concluded that the fraction potentiated the activity

of LAK cells and allowed for the reduction in rIL-2, thus

minimizing the toxicity of rIL-2 therapy (20). Other groups

of researchers reported almost identical findings (a 10-fold

potentiation) and concluded that astragalus is effective in

potentiating IL-2-generated LAK cell cytotoxicity in vitro

(21,22). Astragalus was also found to enhance the secretion

of tumor necrosis factor (TNF) from human peripheral

blood mononuclear cells (PBMCs). A polysaccharide

fraction (molecular weight 20,000–25,000) increased secretion

of TNF- and TNF- after isolation of adherent and

non adherent mononuclear cells from PBMCs (23).

Other investigations support the role of astragalus

polysaccharides as immunomodulating agents.

In an in vitro study, astragalus polysaccharides significantly

induced the proliferation of BALB/c mouse

splenocytes resulting in subsequent induction of interleukin

1 and tumor necrosis factor- and the activation

of murine macrophages. The researchers concluded

32 Upton

that astragalus had an intermediate-to-high affinity

for membrane immunoglobulin (Ig) of lymphocytes

(24).

Cardiovascular Effects

In animal studies, astragalus or its compounds were reported

to elicit antioxidant (25), mild hypotensive (26),

and both positive (27) (50–200 g/mL) and negative

(30 g/mL) inotropic activity (28). The inotropic activity

was reported to be due to the modulation of Na+–K+

ATPase in a manner similar to strophanthin K. Antioxidant

(29), calcium channel blocking (30), and fibrinolytic

activity (31) have been reported in in vitro studies. Astragaloside

IV was studied for potential cardioactivity.

Various effects have been reported. Intravenous administration

of astragaloside IV reduced the area of myocardial

infarct and reduced plasma creatine phosphokinase

release in dogs subjected to 3-hour ligation and increased

coronary blood flow in anesthetized dogs. In isolated rat

heart perfusion investigations, astragaloside IV significantly

improved (P < 0.01) postischemic heart function

and reduced creatine phosphokinase release from the myocardium.

In addition, coronary blood flow during baseline

perfusion and reperfusion in ischemic rat hearts was

increased, while reperfusion damage was decreased. This

activity was shown to be at least partially attributable to

coronary dilation via an increase in endothelium-derived

nitric oxide. Antioxidant activity via an increase in superoxide

dismutase (SOD) activity has also been reported for

astragalus and is considered to contribute to its cardioprotective

effects (32). Astragaloside IV was also shown

to significantly attenuate blood–brain barrier permeability

in a rat ischemia/reperfusion model (33).

Hepatoprotective Effects

Hepatoprotective effects against numerous hepatotoxic

agents (e.g., acetaminophen, carbon tetrachloride, and Escherichia

coli endotoxin) have been reported in both animal

and in vitro studies. In these experiments, improvement

in histological changes in hepatic tissue, including

fatty infiltration, vacuolar degeneration, and hepatocellular

necrosis, was reported. These effects may be associated

with saponin fractions (34). In one clinical study of

hepatitis B patients, concomitant use of astragalus with

lamivudine and -2b interferon showed greater efficacy

than with lamivudine alone (35).

Systemic Lupus Erythematosus

Astragalus was also studied for its ability to affect natural

killer (NK) cell activity, using an enzyme-release assay.

The NK cell activity of PBMCs from 28 patients with systemic

lupus erythematosus (SLE) was increased after in

vitro incubation with an undefined astragalus preparation.

Low levels of NK cell activity were correlated with

disease activity. PBMCs from patients with SLE had significantly

decreased NK cell activity as compared with

those from healthy donors. The extent of stimulation by

the astragalus preparation was related to the dose and

length of the preincubation period (36). Despite its use as

an immune-enhancing agent, which would normally be

considered contraindicated in autoimmune disorders, investigation

of astragalus may be warranted as evidence

suggests that it elicits significant anti-inflammatory activity

and improves ratios and function of T lymphocytes in

SLE (37).

Viral Infections

Prophylaxis against flu and modulation of endogenously

produced interferon have been reported in several animal

studies utilizing astragalus alone (6).

Other Effects

In a new line of investigation for astragalus, two triterpenes

(astragaloside II and isoastragaloside I) were

shown to alleviate insulin resistance and glucose intolerance

in mice. The two compounds selectively increased

adiponectin secretion on primary adipocytes and potentiated

the effects of the insulin-sensitizer rosiglitazone.

Chronic administration of the compounds (specific details

lacking) to both dietary and genetically obese mice

resulted in a significant increase in serum adiponectin, resulting

in an alleviation of hyperglycemia, glucose intolerance,

and insulin resistance. These effects were diminished

in mice lacking adiponectin (38).

One study showed that a liquid extract of astragalus

(2 g/mL/intravenous) retarded the progression of renal

fibrosis in a manner similar to the angiotensin-II-receptor

antagonist losartan. The study reported that like losartan,

astragalus decreased deposition of fibronectin and

type-I collagen by significantly reducing the expression of

transforming growth factor-1 and -smooth muscle actin

(P < 0.05) (39).

Astragalus was investigated for its potential effect

of reducing atopic dermatitis in mice. Using prednisolone

(3 mg/kg/day) as a comparator, an astragalus water extract

was administered orally at 100 mg/kg. Astragalus

significantly reduced the severity of chemically induced

inflammation (2,4-dinitrofluorobenzene) to a degree similar

to the comparator but, unlike prednisolone, did not

inhibit interleukin-4 production (40).

CLINICAL STUDIES

There are both English and Chinese language studies on

astragalus. As with much of the literature regarding Chinese

herbs, there are few clinical data of high methodological

quality. In addition, a positive publication bias

regarding Chinese literature has been reported (41), while

in primary American medical literature, a negative publication

bias against dietary supplement studies has been

reported (42).

Immunomodulatory Effects

Cancer

Among modern herbal practitioners, astragalus is recommended

as an immune supportive botanical in conjunction

with conventional chemo and radiation therapies for

cancer. There is a common belief and some clinical and

preclinical evidence that astragalus both reduces side effects

associated with conventional cancer therapies and

can potentiate the effects of certain therapies. The available

evidence is not strong enough to recommend astragalus

as a standard part of conventional cancer care. However,

Astragalus 33

its demonstrated safety, lack of negative interaction with

conventional therapies, and its putative benefit in building,

preserving, and restoring immunocompetency before

and after conventional therapies warrant specific study.

There is also potential for use of both oral and injectable

preparations, the latter of which are not approved in North

America but are widely used throughout Asia.

In one clinical study, an astragalus drip (20 mL in

250 mL saline solution daily for 84 days) was administered

to cancer patients (n = 60). Compared with the control

group (no astragalus), those in the astragalus group

showed a slower rate of tumor progression, a lower rate

of reduction in peripheral leukocytes and platelets, reduction

in suppressor CD8s, improved CD4/CD8 ratios,

increased IgG and IgM, and better Karnofsky scores (43).

In addition to its use alone, both as a primary treatment

and as an adjunct to conventional cancer therapies,

astragalus is most often combined with other similar acting

immune-enhancing plants. A number of randomized

prospective clinical studies of cancer patients were conducted

using a combination of astragalus and ligustrum

(Ligustrum lucidum) (undisclosed quantities) with positive

results, such as mortality reduction in breast and lung

cancer patients (44). These effects, of course, must be considered

to be due to the cumulative effects of the two

botanicals and cannot be presumed to occur with astragalus

alone but are more consistent with the manner in

which astragalus is used in TCM.

An early clinical trial reported that 53 cases of

chronic leukopenia responded favorably to an astragalus

extract (1:1; 2 mL daily intramuscularly for 1–2 weeks).

Improvements in symptoms and white blood cell counts

were observed, but specific data were lacking (34).

Cardiovascular Effects

Various cardioactive properties have been reported for astragalus,

and astragalus is widely used in the treatment of

both chronic and acute cardiovascular disease in China.

In one study, 92 patients with ischemic heart disease were

given an unidentified preparation of astragalus. Marked

relief from angina pectoris and other improvements as

measured by electrocardiogram (ECG) and impedance

cardiogram were reported. Improvement in the ECG index

was reported as 82.6%. Overall improvement was significant

as compared with the control group (P<0.05) (45).

A similar result in cardiac performance was reported by

other groups of researchers. In one study, 43 patients were

hospitalized within 36 hours of acute myocardial infarct.

After administration of an astragalus preparation (undefined

profile), the ratio of pre ejection period/left ventricular

ejection time was decreased, the antioxidant activity of

SOD of red blood cells was increased, and the lipid peroxidation

content of plasma was reduced (46). In another experiment,

20 patients with angina pectoris were given an

undefined astragalus preparation. Cardiac output, as measured

by Doppler echocardiogram, increased from 5.09 °æ

0.21 to 5.95 °æ 0.18 L/min 2 weeks after administration

of astragalus (P < 0.01). In this study, neither improvement

in left ventricular diastolic function nor inhibition of

adenosine triphosphate was observed (47). Intravenous

administration of astragalus (undefined preparation) was

reported to significantly shorten the duration of ventricular

late potentials in cardiac patients (39.8 °æ 3.3 ms vs.

44.5 °æ 5.9 ms; P < 0.01) (48).

In another investigation, astragaloside IV (intravenous;

unspecified amount) was given to patients with

congestive heart failure for 2 weeks. Improvement in

symptoms such as tightness in the chest, difficult breathing,

and reduced exercise capacity were reported. Radionuclide

ventriculography showed that left ventricular

modeling improved and left ventricular end-diastolic and

left ventricular end-systolic volume diminished significantly.

The authors concluded that astragaloside IV is an

effective positive inotropic agent (49), an action supported

by others (27).

Hepatoprotective Effects

In China, astragalus is widely used in the treatment of

chronic hepatitis where reductions in elevated liver enzymes

and improvements in symptoms in humans have

been reported. This activity is stated to be associated with

polysaccharides that increase interferon production (35).

Viral Infections

According to one English language review of the Chinese

literature, a prophylactic effect against the common cold

was reported in an epidemiological study in China involving

1000 subjects. Administration of astragalus, given either

orally or as a nasal spray, reportedly decreased the

incidence of disease and shortened cold duration. Studies

exploring this protective effect found that oral administration

of the preparation to subjects for 2 weeks enhanced

the induction of interferon by peripheral white blood cells.

Levels of IgA and IgG antibodies in nasal secretions were

reported to be increased following 2 months of treatment

(34). The effect of astragalus on the induction of interferon

was studied in a placebo-controlled study involving 28

people. Fourteen volunteers were given an extract equivalent

to 8 g of dried root per day and the rest were given

placebos. Blood samples were drawn before treatment,

then 2 weeks and 2 months after treatment. Interferon

production by leukocytes was statistically increased after

both time periods (P < 0.01) in the astragalus group but

not the control group (50). In another study, astragalus

was shown to potentiate the effects of interferon (rIFN-1)

in patients with chronic cervicitis (51).

Dosages

Crude root: 9–30 g daily as a decoction (52).

Decoction: 0.5–1 L daily.

SAFETY PROFILE

Side Effects

None cited in the literature.

Contraindications

None cited in the literature.

Precautions

There is some evidence to suggest that astragalus and its

putative anti-inflammatory effects are beneficial in those

with autoimmune conditions such as lupus. However, astragalus

should be used cautiously for the treatment of

34 Upton

autoimmune diseases or in conjunction with immunosuppressive

therapies. Because immunostimulating polysaccharides

may stimulate histamine release, allergic symptoms

may be aggravated by the use of astragalus. This,

however, has not been reported in the literature or from

clinical use. According to the principles of TCM, astragalus

should not be used during acute infectious conditions

unless under the care of a qualified TCM practitioner.

Interactions

Both positive and negative interactions may occur. Astragalus

potentiates the effects of acyclovir (53); IL-2, -20,

-21; and rIFN-1 and -2 therapies (50,51). Because of its immuno promoting

effects, astragalus may be incompatible

with immunosuppressive agents in general.

Pregnancy, Mutagenicity, and Reproductive Toxicity

According to one review, astragalus is reported to have no

mutagenic effects (54).

Lactation

Based on an authoritative review of the available pharmacologic

and toxicologic literature, no limitation is to be

expected (6,34,54).

Carcinogenicity

Studies suggest an anticarcinogenic activity.

Influence on Driving

Based on the available pharmacologic and toxicologic literature,

no limitation is to be expected (6,34,54).

Overdose and Treatment

Specific data are lacking.

Toxicology

Based on a review of the available data and the experience

of modern practitioners, astragalus can be considered

a very safe herb even when taken within its large

dosage range. Investigations of specific fractions including

flavonoids, polysaccharide, and triterpene similarly

show little toxicity (14,34,54).

Regulatory Status

In the United States, astragalus is regulated as a dietary

supplement.

CONCLUSIONS

Astragalus is one of the most frequently used herbal

medicines throughout Asia and is a very popular botanical

used in western herbal supplements. In China, astragalus

is used for a myriad of purposes relating to its

high regard as a strengthening tonifier, immune modulator,

anti-inflammatory, and anti-hepatotoxic. In the West,

astragalus figures prominently in immune supportive formulas.

Despite its popularity, there are few clinical trials

regarding its use. There is some evidence to support

the oral administration of astragalus for the prevention of

colds and upper respiratory infections, and as an adjunct

to conventional cancer therapies. These are very common

indications for which astragalus is applied by herbal practitioners.

For its use in cancer therapies, there are no definitive

guidelines. The modern experience of practitioners

together with the limited clinical and preclinical data

pointing to an immunomodulatory effect suggests that

there may be some value for these indications, including

the concomitant use of astragalus to reduce doxorubicininduced

immune suppression. However, more specific investigation

in this area is needed.

Regarding its putative immunomodulating effects,

the following mechanisms of action have been proposed:

restoration of immune function, increased stem cell generation

of blood cells and platelets, lymphocyte proliferation,

rise in numbers of antibody-producing spleen cells,

potentiation of rIL-2 and rIFN-1 and -2 immunotherapy,

enhancement of phagocytic activity by macrophages and

leukocytes, and increased cytotoxicity by NK cells.

Potential benefits to cardiovascular health, including

relief from angina and congestive heart failure and

improvement in clinical parameters following acute myocardial

infarct, have been reported. Limited animal studies

suggest that astragalus enhances coronary blood flow,

may potentiate the release of nitric oxide, and potentiates

the effects of endogenous antioxidant systems (e.g., SOD).

In Asia, astragalus is also used in conjunction with

conventional medical treatments for hepatitis. Both animal

and in vitro studies offer support for such treatment.

As in the use of astragalus in cancer therapies, further

clinical trials are required.

Though methodologically sound clinical trials for

astragalus are generally lacking, natural health practitioners

have a generally high regard for its use as a prophylactic

against infectious disease and for its ability to build,

maintain, and restore immunocompetency when used as

a part of conventional cancer therapies. In addition to the

very limited number of formal clinical studies that are

available in English language sources, the published medical

literature on astragalus has to be considered cautiously,

as a number of the supporting studies utilize injectable

preparations of isolated fractions that are not consistent

with the oral use of astragalus supplements. Still, the existing

data do support many of the traditional uses for

which astragalus has been employed for centuries.

REFERENCES

1. Huang QS, Lu GB, Guo JH. Studies on the polysaccharides of

Astragalus membranaceus. Yao Xue Tong Bao 1981; 16(18):58.

2. Huang QS, Lu GB, Guo JH. Studies on the polysaccharides

of “huang qi” Astragalus mongolicus. Yao Xue Xue Bao 1982;

17(3):200–206.

3. Cao ZZ, Yu JH, Gan LX, et al. The structure of astramembrangenin.

Hua Xue Xue Bao 1983; 41(12):1137–1145.

4. Cao ZZ, Yu JH, Gan LX, et al. The structure of astramembrannins.

Hua Xue Xue Bao 1985; 43(6):581–585.

5. Kitagawa I,Wang HK, Yoshikawa M. Saponin and sapogenol

XXXVII: chemical constituents of astragali radix, the root of

Astragalus membranaceus Bunge, astragalosides VII and VIII.

Chem Pharm Bull 1983; 31(2):716–722.

6. Upton R. ed. Astragalus Root. Monograph. Santa Cruz, CA:

American Herbal Pharmacopoeia, 1999.

7. Xu F, Zhang Y, Xiao SY, et al. Absorption and metabolism of

astragali radix decoction: in silico, in vitro, and a case study

in vivo. Drug Metab Dispos 2006; 34:913–924.

Astragalus 35

8. Zhang WD, Zhang C, Liu RH, et al. Preclinical pharmacokinetics

and tissue distribution of a natural cardioprotective

agent astragaloside IV in rats and dogs. Life Sci 2006; 79:808–

815.

9. Zhang WD, Zhang C, Liu RH, et al. Determination of astragaloside

IV, a natural product with cardioactivity, in plasma,

urine and other biological samples by HPLC coupled with

tandem mass spectrometry. J Chromatogra B 2005; 822;170–

177.

10. Su D, Li HY, Yan HR, et al. Astragalus improved cardiac

function of adriamycin-injured rat hearts by upregulation of

SERCA2a expression. Am J Chin Med 2009; 37(3):519–529.

11. Chu DT, Wong WL, Mavligit GM. Immunotherapy with

Chinese medicinal herbs I: immune restoration of local

xenogeneic graft-versus-host reaction in cancer patients by

fractionated Astragalus membranaceus in vitro. J Clin Lab

Immunol 1988; 25(3):119–123.

12. Chu DT, Wong WL, Mavligit GM. Immunotherapy with

Chinese medicinal herbs II: reversal of cyclophosphamideinduced

immune suppression by administration of fractionated

Astragalus membranaceus in vivo. J Clin Lab Immunol

1988; 25:125–129.

13. Chu DT, Sun Y, Lin JR. Immune restoration of local xenogeneic

graft-versus-host reaction in cancer patients in vitro

and reversal of cyclophosphamide-induced immune suppression

in the rat in vivo by fractionated Astragalus

membranaceus. Chin J Integr Trad West Med 1989; 9(6):

326–354.

14. Chu DT, Lepe-Zuniga J,Wong WL, et al. Fractionated extract

of Astragalus membranaceus, a Chinese medicinal herb, potentiates

LAK cell cytotoxicity generated by low dose of recombinant

interleukin-2. J Clin Lab Immunol 1988; 26(3):183–187.

15. Shimizu N, Tomoda M, Kanari M, et al.An acidic polysaccharide

having activity on the reticuloendothelial system from

the root of Astragalus mongholicus. Chem Pharm Bull 1991;

39(11):2969–2972.

16. Tomoda M, Shimuzu N, Ohara N, et al.Areticuloendothelial

system-activating glycan from the roots of Astragalus membranaceus.

Phytochemistry 1992; 31(1):63–66.

17. Rou M, Renfu X. The effect of Radix Astragali on mouse

marrow hemopoiesis. J Tradit Chin Med 1983; 3(3):199–204.

18. Na D, Liu FN, Miao ZF, et al. Astragalus extract inhibits

destruction of gastric cancer cells to mesothelial cells by antiapoptosis.

World J Gastroenterol 2009; 15(5):570–577.

19. Chu DT, Sun Y, Lin JR, et al. F3, a fractionated extract of

Astragalus membranaceus, potentiates lymphokine-activated

killer cell cytotoxicity generated by low dose recombinant

interleukin-2. Chin J Integr TradWest Med 1990; 10(1):34–36.

20. Chu DT, Lin JR,Wong WL. The in vitro potentiation of LAK

cell cytotoxicity in cancer and AIDS patients induced by F3, a

fractionated extract of Astragalus membranaceus. Chung Hua

Chung Liu Tsa Chih 1994; 16(3):167–171.

21. Wang Y, Qian XJ, Hadley HR, et al. Phytochemicals potentiate

interleukin-2 generated lymphokine-activated killer cell

cytotoxicity against murine renal cell carcinoma. Mol Biother

1992; 4(3):143–146.

22. Zhou S, Lu Z, Wang Y, et al. Study on the antineoplastic

activity of astragalus polysaccharide. Yao Wu Sheng Wu Ji

Shu 1995; 2(2):22–25.

23. Zhao KW, Kong HY. Effect of astragalan on secretion of tumor

necrosis factors in human peripheral blood mononuclear

cells. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 1993;

13(5):263–265.

24. Shao BM, Xu W, Dai H, et al. A study on the immune receptors

for polysaccharides from the roots of Astragalus membranaceus,

a Chinese medicinal herb. Biochem Biophys Res

Commun 2004; 320;1103–1111.

25. Lei C, Yue H, Chen Y, et al. Effects of astragalus saponins

on ischemic scope, epicardial ECG, myocardial enzymes in

acute myocardial infarcted dog heart. Baiqiuen Yike Daxue

Xuebao 1995; 21(2):111–113.

26. Hikino H, Funayama S, Endo K. Hypotensive principle of

astragalus and hedysarum roots. Planta Med 1976; 30:297–

302.

27. Zhong G, Jiang Y, Wei Y, et al. Positive inotropic action of

Astragalus membranaceus saponins on isolated working heart.

Baiqiuen Yike Daxue Xuebao 1994; 20(5):448–449.

28. Wang Q, Li Y, Qi H, et al. Inotropic action of Astragalus

membranaceus Bunge saponins and its possible mechanism.

Zhongguo Zhongyao Zazhi 1993; 17(9):557–559.

29. Sun C, Zhong G, Zhan S, et al. Study on antioxidant effect

of astragalus polysaccharide. Zhongguo Yaolixue Tongbao

1996; 12(2):161–163.

30. Guo Q, Peng T, Yang Y, et al. Effect of drugs on Ca2+ influx

andCVB3-RNAreplication in cultured rat heart cells infected

with CVB3. Virol Sin 1996; 11(1):40–44.

31. Zhang WJ, Wojta J, Binder BR. Regulation of the fibrinolytic

potential of cultured human umbilical vein endothelial

cells: astragaloside IV down regulates plasminogen

activator inhibitor-1 and up regulates tissue-type

plasminogen activator expression. JVasc Res 1997; 34(4):273–

280.

32. Zhang WD, Chen H, Zhang C, et al. Astragaloside IV from

Astragalus membranaceus shows cardioprotection during myocardial

ischemia in vivo and in vitro. Planta Med 2006;

72:4–8.

33. QuYZ, Li M, Zhao YL, et al. Astragaloside IV attenuates cerebral

ischemia-reperfusion-induced increase in permeability

of the blood brain barrier in rats. Eur J Pharmacol 2009;

606:137–141.

34. Chang HM, But P. Pharmacology and Applications of

Chinese Materia Medica. Singapore: World Scientific,

1987.

35. Wu L, Liu H, Xue P, et al. Influence of a triplex superimposed

treatment on HBV replication and mutation during treating

chronic hepatitis B. Zhonghua Shi Yan He Lin Chuang Bing

Du Xue Za Zhi 2001; 15(3):236–238.

36. Zhao XZ. Effects of Astragalus membranaceus and Tripterygium

hypoglaucum on natural killer cell activity of peripheral

blood mononuclear in systemic lupus erythematosus.

Zhongguo Zhong Xi Yi Jie He Za Zhi 1992; 12(11):645, 669–

671.

37. Pan HF, Fang XH, Li WX, et al. Radix Astragali: A promising

new treatment option for systemic lupus erythematosus.

Med Hypothesis 2008; 71(2)311–312.

38. Xu A, Wang HB, Hoo RLC, et al. Selective elevation of

adiponectin production by the natural compounds derived

from a medicinal herb alleviates insulin resistance and

glucose intolerance in obese mice. Endocrinology 2009;

150(2):625–633.

39. Zuo C, Xie XS, Qiu HY, et al. Astragalus mongholicus ameliorates

renal fibrosis by modulating HGF and TGF in rats with

unilateral ureteral obstruction. J Zhejiang Univ Sci B 2009;

10(5):380–390.

40. Lee SJ, Oh SG, Seo SW, et al. Oral administration of Astragalus

membranaceus inhibits the development of DNFBinduced

dermatitis in NC/Nga mice. Biol Pharm Bull 2007;

30(8):1468–1471.

41. Vickers A, Goyal N, Harland R, et al. Do certain countries

produce only positive results? A systematic review of controlled

trials. Controlled Clin Trials 1998; 19:159–166.

42. Kemper KJ, Hood KL. Does pharmaceutical advertising affect

journal publication about dietary supplements? BMC

Complement Altern Med 2008; 8(11):1–8.

43. Duan P, Wang ZM. Clinical study on effect of astragalus in

efficacy enhancing and toxicity reducing of chemotherapy in

patients of malignant tumors. Zhongguo Zhong Xi Yi Jie He

Za Zhi 2002; 22(7):515–517.

36 Upton

44. Morazzoni P, Bombardelli P. Astragalus membranaceus (Fisch)

Bunge; Scientific Documentation 30. Milan, Italy: Indena

SpA, 1994;1–18.

45. Li SQ, Yuan RX, Gao H. Clinical observation on the treatment

of ischemic heart disease with Astragalus membranaceus. Kuo

Chung Hsi I Chieh Ho Tsa Chih 1995; 15(2):77–80.

46. Chen LX, Liao JZ, Guo WQ. Astragalus membranaceus on left

ventricular function and oxygen free radical in acute myocardial

infarction patients and mechanism of its cardiotonic

action. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 1995;

15(3):141–143.

47. Lei ZY, Qin H, Liao JZ. Action of Astragalus membranaceus

on left ventricular function of angina pectoris. Chung Kuo

Chung Hsi I Chieh Ho Tsa Chih 1994; 14(4):199–202.

48. Shi HM, Dai RH, Wang SY. Primary research on the clinical

significance of ventricular late potentials (VLPs), and the impact

of mexiletine, lidocaine, and Astragalus membranaceus

on VLPs. Chung Hsi I Chieh Ho Tsa Chih 1991; 11(5):

265–267.

49. Luo HM, Dai RH, Li Y. Nuclear cardiology study on effective

ingredients of Astragalus membranaceus in treating heart

failure. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 1995;

15(12):707–709.

50. Hou Y, Zhang Z, Su S, et al. Interferon induction and lymphocyte

transformation stimulated by Astragalus membranaceus

in mouse spleen cell cultures. Zhonghua Weisheng Wuxue

Hemian Yixue Zazhi 1981; 1(2):137–139.

51. Qian ZW, Mao SJ, Cai XC, et al. Viral etiology of chronic

cervicitis and its therapeutic response to -recombinant interferon.

Chin Med J 1990; 103:647–651.

52. Radix Astragali (huangqi). Pharmacopoeia of the People’s

Republic of China. Vol 1. Beijing, China: Chemistry and Industry

Press, 1997:442.

53. Zuo L, Dong X, Sun X. The curative effects of Astragalus

membranaceus Bunge (A-6) in combination with acyclovir on

mice infected with HSV-1. Virol Sin 1995; 10(2):177–179.

54. Wagner H, Bauer R, Peigen X, et al. Radix Astragali [Huang

Qi]. Chin Drug Monogr Anal 1997; 1(8):18.

Black Cohosh

Glossary, HerbsSuccess Chemistry Staff

Black cohosh is a native eastern North American plant that

was used as traditional medicine by Native Americans.

 

Extracts of the roots and rhizomes were used for analgesic,

sedative, and anti-inflammatory properties.More recently,

root and rhizome black cohosh preparations have had a

rich clinical history, spanning almost 60 years of study.

These studies have primarily focused on relieving climacteric

symptoms associated with menopause as a possible

alternative to classical hormone or estrogen replacement

therapy.

 

BACKGROUND

The common name for black cohosh [Actaea racemosa L.

syn., Cimicifuga racemosa (L.) Nutt. (Ranunculaceae, Buttercup

Family)] originated with North American Indians.

The term cohosh is thought to be an Algonquian

word meaning “rough,” with reference to the texture

of the thick, knotted roots and underground stems (rhizomes).

A New World plant used by Native Americans,

it was most abundant in the Ohio River Valley, but it

could also be found from Maine to Wisconsin, south

along the Allegheny Mountains to Georgia, and west to

Missouri.

Various common names have been used to refer to

black cohosh, including black snakeroot, bugbane, rattleroot,

squawroot, and macrotys. It is a member of the Ranunculaceae

or Buttercup family, which includes other

medicinal plants such as aconite, goldenseal, and pulsatilla.

It has been known by the scientific name C. racemosa

and recently has been assigned to A. racemosa. The

generic name Cimicifuga derives from the Latin cimex

(a kind of bug) and fugare (to put to flight), which is

perhaps indicative of the use of some strongly smelling

close relatives to repel insects. The specific epithet racemosa

refers to the flowering stalk, termed a raceme. The

name rattleroot is indicative of the rattling sound made by

the dry seeds in their pods. This plant prefers the shade

of rich open hardwood forests, but it will tolerate some

sunny spots.

 

Black cohosh has been used clinically for relief of

climacteric symptoms for more than 60 years, and its popularity

in the United States as a botanical dietary supplement

has increased due to the recently recognized potential

risks associated with classical estrogen replacement

therapy or hormone replacement therapy (1,2). The part

of the black cohosh plant used in medicinal preparations

is the root and rhizome. It was officially recognized in the

United States Pharmacopeia (USP) from the first edition in

1820 to 1936 and in the National Formulary from 1936 to

1950. The eclectic physicians used a preparation of black

cohosh called macrotys. It was considered one of the bestknown,

specific medicines for heavy, tensive, and aching

pains as it was noted to have a direct influence on the

female reproductive organs.

While the mechanism of action has not been completely

elucidated, recent literature suggests that alleviation

of climacteric symptoms is mediated through neurotransmitter

regulation and not through classical estrogen

receptor (ER) endocrine pathways (3,4).

CHEMISTRY

More than 60 triterpene glycosides, most with a 9,19

cycloartane skeleton, and unique to Actaea spp., have

been reported from the roots and rhizomes of A. racemosa

(5,6). The compound 23-epi-26-deoxyactein (formerly

27-deoxyactein) is the constituent usually selected for

standardization of commercial products based on its

abundance in the roots and rhizomes (7–12). The pharmacokinetics

of 23-epi-26-deoxyactein in serum and urine has

recently been reported (13). While triterpenes are structurally

similar to steroids and possess a broad range of

biological activity (14–17), no significant ligand binding

affinity was found toward ER- in the evaluation of 23-

epi-26-deoxyactein, cimiracemoside F and cimicifuga,

and their respective aglycones (18). This, coupled with

the lack of demonstrated estrogenic activity in A. racemosa

extracts, has called into question the notion that black cohosh

acts through direct ER binding by the triterpenes, as

has been hypothesized (19–23).

In addition to the triterpene saponins, the roots and

rhizomes of black cohosh also contain a number of aromatic

acids/polyphenols that possess a wide array of biological

activities (5,24–26). Caffeic acid, which is found

widely across all species of flowering plants, has shown

pregnant mare anti gonadotropin activity (27–29), rat uterine

antispasmodic activity (30), and smooth muscle relaxant/

antispasmolytic activity in rats (31) and guinea

pig ileum (32). Ferulic acid, also more or less ubiquitous

among flowering plants, has demonstrated luteinizing

hormone (LH) release inhibition (33), follicle-stimulating

hormone (FSH) release stimulation (33), antiestrogenic activity

(34), prolactin stimulation in cows (35) and inhibition

in rats (33), and uterine relaxant/antispasmolytic

activity in rats (36). Fukinolic acid produced an estrogenic

effect on MCF-7 cells with reference to estradiol

Black Cohosh

(37). A more recent study refuted this effect and demonstrated

a lack of estrogenic effect for 10 other phenolic

esters, many of which are unique to Actaea spp. (caffeoyl glycolic

acid; 2-caffeoylquinic acid (cimicifuga acid

D); 3,4-dihydroxyphenyl caffeate (petasiphenone); 3,4-

dihydroxyphenyl-2-oxopropyl isoferulic (cimici phenol);

3,4-dihydroxyphenyl isoferulic (cimici phenone); cimicifuga

acids A, B, E, F; and folic acid) from black

cohosh (38).

Studies on the phenolic acid constituents of black

cohosh have shown antioxidant activity (24,39) that may

correlate with or prove useful in the determination of the

mechanism of action of black cohosh. In addition, a number

of plant sterols and fatty acids, generally regarded as

ubiquitous in the plant kingdom, are contained in the roots

and rhizomes for which the biological activities probably

do not relate to the mechanism of action of black cohosh

(5). In the past 5 years, novel guanidine alkaloids have

been isolated from A. racemosa underground parts (40,41).

New phytochemical methodology called pH zone refinement

gradient centrifugal partitioning chromatography

coupled with a sensitive liquid chromatography–mass

spectral dereplication method led to the identification of

N-(omega)-methylserotonin as a potential active principle

with serotonergic properties (41). Alkaloids have also been

reported from other Actaea spp. roots and rhizomes (42,43).

There has been some debate over the occurrence

of the weakly estrogenic compound formononetin in the

plant (44–49). Although there has been at least one report

of its occurrence in A. racemosa (46), prior studies using

plant material collected from different sites in the Eastern

United States at different times of the year failed to find

formononetin (47,48). More recent studies on both commercial

black cohosh products and wild-crafted material,

incorporating both high-performance liquid chromatography

with mass spectral and photodiode array detection,

confirmed the prior findings of no detectable formononetin

in black cohosh (8,49).

BOTANICAL DESCRIPTION

A. racemosa syn. C. racemosa is an erect, smooth-stemmed

perennial 1–2.5 m in height. Large compound leaves are

alternately arranged and triternate on short clasping petioles.

Basal leaf petioles are grooved in young specimens.

This shallow, narrow sulcus in A. racemosa disappears as

the petiole enlarges, whereas it remains present throughout

the life of the two related eastern North American

species, A. cordifolia DC syn. C. rubifolia Kearney and

A. podocarpa DC syn. C. americana Michx (50). Terminal

leaflets of A. racemosa are acute and glabrous with sharp

serrated margins, often trilobate, occasionally bilobed.

Fruits are ovoid follicles occurring sessile on the pedicel.

The flowering portion, the raceme, is a long wandlike

structure with showy white flowers. The flowers possess

numerous characteristic stamen and slender filaments

with distinctive white anthers (51). The roots and rhizomes

are branched and knotted structures with a dark brown

exterior and are internally white and mealy or brown and

waxy. The upper rhizome surface has several buds and numerous

large stem bases terminated frequently by deep,

cup-shaped, radiating scars, each of which show a radiate

structure or less frequently fibrous strands. Lower and lateral

surfaces exhibit numerous root scars and a few short

roots. The fracture is horny, the odor slight, and the taste

bitter and acrid (52).

Black Cohosh EFFECTS ON CLIMACTERIC SYMPTOMS

RELATED TO MENOPAUSE

With a history of clinical study spanning almost 60 years,

mainly in Europe (53), black cohosh is one of the more popular

alternatives to hormone replacement therapy. Most

of the clinical research over this span has been performed

on the product known as Remifemin R , whose formula

has changed over the years. However, a number of other

commercial formulations are also available. In 2007, black

cohosh was the 50th best-selling dietary supplement in

the United States with sales of approximately $52 million

(USD), according to the Nutrition Business Journal (54).

Black cohosh clinical study outcomes have been

evaluated using a variety of tools, including self- or physician

assessments of symptom scores and physiological

parameters. Typical measurements include psychological,

neurovegetative, somatic, and physiological markers of

menopause or relief from the climacteric symptoms of

menopause. As in all clinical trials, study design is vital,

so studies that are adequately powered, incorporate

proper controls, and are designed to address confounders

relevant to climacteric symptoms such as the placebo

effect and botanical product quality should be given

more weight than studies that are not as well designed

(55–59).

Placebo effects in menopausal trials are generally

large (60) and reflect underlying fluctuations of symptoms.

Therefore, any well-designed study must adjust

the appropriate variables (i.e., study duration, number

of subjects (n), and/or dosage) to account for such an effect.

In the evidence-based medicine model, the gold standard

in terms of efficacy involves randomized, controlled

trials (RCTs). Many RCTs on black cohosh exist. When

high-quality studies are combined, more than 3000 subjects

have been randomized, with the more recent studies

adding layers of design sophistication. For example,

double-blind, multicenter, placebo-controlled trials that

provide details regarding clinical material specifications

are becoming more prevalent (55–60).

A recent phase III, double-blind, randomized,

placebo-controlled crossover trial of the effectiveness of

black cohosh for the management of hot flashes was conducted

over two 4-week periods (one capsule, 20 mg bid)

(61). The study used a daily hot flash diary and found

that subjects receiving the black cohosh material reported

a mean 20% decrease in hot flash score (comparing the

fourth treatment week to the baseline week) versus a 27%

decrease for patients on placebo (P = 0.53), mean hot flash

frequency was reduced 17% in the black cohosh group and

26% on placebo (P = 0.36). Thus, the authors concluded

that the study did not provide any evidence that black

cohosh reduced hot flashes more than the placebo. Critics

of the study point to the short duration and low dose as

potential confounders of the results.

The Herbal Alternatives for Menopause trial or

HALT trial compared the efficacy of 160 mg daily black

62 Fabricant et al.

cohosh against several other interventions (200 mg daily

multi botanical with black cohosh and nine other ingredients;

200 mg daily multi botanical plus dietary soy counseling;

0.625 mg daily conjugated equine estrogen with or

without 2.5 mg medroxyprogesterone acetate daily; and

placebo) in 351 menopausal and postmenopausal women

of ages 45–55 years with two or more vasomotor symptoms

per day. Results did not suggest efficacy for any of

the herbal interventions when compared with placebo at

any time point over the 1-year course of the study (62).

The Jacobson study (63), spanning only 60 days of

treatment, suggests that the short study duration may

have limited the findings (60). In addition, all the study

participants had a history of breast cancer. The authors

reported that the median number of hot flashes decreased

27% in both the placebo and black cohosh groups. No significant

differences were observed between groups. Thus,

black cohosh, on the basis of this study, was no more effective

than placebo in the treatment of hot flashes. The

source and formulation of the extract used in this study

was not specified. A more recent open-label study that

treated breast cancer survivors with either Tamoxifen R or

a combination of BNO 1055, a proprietary black cohosh extract,

with Tamoxifen suggested a reduction in the number

and severity of hot flashes in the combination treatment

group (64).

In another randomized, double-blind, placebo controlled

study that lasted 12 weeks, black cohosh was

compared with standard conjugated estrogen (CE) therapy

(0.625 mg/daily). Patients’ physical and psychological

symptoms were measured every 4 weeks. The end

result of the study was that the patients treated with

black cohosh had significantly lower index scores on

both the Kupperman menopausal (KM) and the Hamilton

menopausal (HAM-A) scales compared with placebo,

indicating a decrease in severity and frequency of hot

flashes. In addition, this study showed an increase in the

number of estrogenized cells in the vaginal epithelium in

the black cohosh treatment arm, which could indicate an

estrogenic action in this tissue (65).

In 2003, a similar study compared effects of two

different preparations of BNO 1055 extract and CE therapy

on climacteric symptoms and serum markers of

bone metabolism (66). The study outcomes were evaluated

using patient self-assessment (diary and menopause

rating scale), CrossLaps (to measure bone resorption),

bone specific alkaline phosphatase (marker of bone formation),

and endometrial thickness (measured by ultrasound).

Both BNO 1055 extracts were equipotent to CE

therapy and significantly greater than placebo at reducing

climacteric complaints. In addition, the study showed

that both BNO 1055 preparations had beneficial effects

on bone metabolism in serum. Specifically, an increase in

bone-specific alkaline phosphatase and no reduction in

bone resorption were noted indicating an increase in bone

turnover formation. No change in endometrial thickness

was observed in either BNO 1055 treatment groups, but it

was significantly increased with CE therapy. An increase

in superficial vaginal cells was observed in the CE and

both BNO 1055 treatment groups. The authors of the study

hypothesized that the activity of both BNO 1055 preparations

was similar to the effects of selective estrogen receptor

modulating (SERM), that is, Raloxifene R therapy on

bone and neurovegetative climacteric symptoms, without

any uterotrophic effects (66).

A recent high-quality, double-blind, randomized

study evaluated the effects of two dosages (low, 39 mg;

high, 127 mg) of a Remifemin extract on menopausal

symptoms. Effectiveness was measured using the KM index,

self-assessment depression scale (SDS), clinical global

impression scale (CGI), serum levels of LH and FSH,

sex hormone–binding globulin, prolactin, 17--estradiol,

and vaginal cytology. Reductions in the KM and SDS indices

were significant. Global efficacy (CGI) was scored

at good to very good in 80% (low dosage) and 90%

(high dosage) of the patients in the treatment groups (67).

No effect on serum hormone levels or vaginal cytology

was shown, prompting the authors of the study to suggest

that black cohosh does not have a direct estrogenic

effect on the serum hormone levels or vaginal epithelium

(68). Two recent open-label studies using unspecified

types of extracts reported reduced KM index scores.

One study reported a significant reduction in 1 month

(69), while the other, which also used the HAM-A scale,

recorded a 90% improvement in climacteric symptoms

in menopausal women after 3 months of black cohosh

administration (70).

Chung and colleagues (71) examined a combination

of black cohosh and St. John’s wort (Gynoplus R ) inamulti center

RCT in 89 peri- or postmenopausal women with

climacteric symptoms. Subjects were treated for 12 weeks

with either the Gynoplus extract or placebo. In addition

to climacteric complaints, investigators also examined effects

on vaginal atrophy, serum hormone levels (FSH, LH),

and lipid profiles [total cholesterol, high-density lipoprotein

(HDL) cholesterol, low-density lipoprotein cholesterol,

and triglyceride]. Significant improvements in climacteric

symptoms and hot flashes, as well as an increase

in HDL, were observed in the Gynoplus group by 4 weeks

and maintained after 12 weeks, but there was no significant

impact on vaginal atrophy.

In a 12-month, randomized, four-arm, double-blind

clinical trial of standardized black cohosh, red clover,

placebo, and 0.625 mg conjugated equine estrogens plus

2.5 mg medroxyprogesterone acetate (conjugated equine

estrogens (CEE) and medroxyprogesterone acetate (MPA);

n = 89), black cohosh did not significantly reduce the

frequency of vasomotor symptoms as compared with

placebo. The primary outcome measures were reduction

in vasomotor symptoms (hot flashes and night sweats) by

black cohosh and red clover compared with placebo; secondary

outcomes included safety evaluation, reduction in

somatic symptoms, relief of sexual dysfunction, and overall

improvement in quality of life. Reductions in number of

vasomotor symptoms after a 12-month intervention were

as follows: black cohosh (34%), red clover (57%), placebo

(63%), and CEE/MPA (94%), with only CEE/MPA differing

significantly from placebo. Secondary measures indicated

that both botanicals were safe as administered. In

general, there were no improvements in other menopausal

symptoms (72).

A 12-week trial investigating the effects of black cohosh

on menopause-related anxiety disorder found no

statistically significant anxiolytic effect of black cohosh

versus placebo.

However, small sample size, choice of

black cohosh preparation, and dosage used may have

Black Cohosh 63

contributed to the negative results according to the study’s

authors (73).

More details of the human studies discussed here,

as well as others, are presented in Table 1.

BIOCHEMISTRY AND FUNCTIONS

Despite the extensive clinical research, the mechanism of

action of black cohosh on menopausal and other symptoms

remains unclear, which is consistent with the varied

results from clinical trials.A Majority of the older literature

suggest a direct estrogenic effect. More recent hypotheses

have proposed an effect on the limbic system (hypothalamus)

or an effect on the neurotransmitters involved in

regulation of this system as being responsible for the activity

of black cohosh. Data fall into the following categories.

Estrogen Receptor Competitive Binding

The first report of ER-binding activity of black cohosh

indicated this as a possible mechanism of action (74).

Additional studies were carried out to substantiate this

purported endocrine activity (75,76). However, a factor

frequently overlooked regarding black cohosh receptor

binding studies is the lipophilic nature of the extracts

tested. Chemically, lipophilic extracts and fractions that

display ER-binding activity are significantly different

from the typical hydroalcoholic extracts used to make

products for human consumption. A lipophilic extract of

the plant showed relatively weak (35 g/mL) ER binding

on rat uteri (75). Another study also confirmed the ERbinding

activity of an unspecified lipophilic subfraction

on ovariectomized (ovx) rat uterine cells, with no binding

activity seen with a hydroalcoholic extract (76).

Recent reports have contradicted the ER-binding

affinity of black cohosh extracts (4,20,22,77,78). A root extract

tested in an in vitro competitive cytosolic ER (from

livers of ovx rat) binding assay with diethylstilbestrol

(50), an inhibitor of estrogen binding, showed a significant

inhibition of estradiol binding in the presence of diethylstilbestrol

(77). However, no binding was demonstrated

for the black cohosh extract. A hydroalcoholic A. racemosa

rhizome extract (50% aqueous ethanol) was assayed for

ER binding in intact human breast cancer cell lines MCF-7

and T-47-D. Again no binding affinity was shown for the

black cohosh extract. However, binding activity was evident

for other hydroalcoholic plant extracts, such as red

clover (78). In another study, a high concentration (200g/

mL) methanol extract of black cohosh displayed no binding

affinity for recombinant diluted ER- and ER- (20).

A study using BNO 1055 showed contrasting results

(79). The extract displayed dose-dependent competition

with radio-labeled estradiol in both a porcine and human

endometrial cytosolic ER ligand-binding assay system.

However, the extract did not displace human recombinant

ER- and ER-. These contradictory findings prompted

the authors to suggest that their product contains estrogenic

compounds that have binding affinity for a putative

ER-. The absence of a direct estrogenic effect was again

confirmed in a human study (21). Postmenopausal Women

took black cohosh extract for 12 weeks followed by a 12-

week washout. Black cohosh demonstrated no effect on

estrogenic markers in serum and no effect on pS2 or cellular

morphology in nipple aspirate fluid (21).

Receptor Expression

As with the receptor-binding assays, the nature of the extract

or fraction is a decisive factor in the expression of

ERs. A lipophilic and hydrophilic black cohosh extract

was studied for luciferase expression in a MCF-7 - and

-ER expressing subclone (80). The lipophilic extract at

35 g/mL activated transcription of the estrogen regulated

genes, while the hydrophilic extract showed no

activity. A recent study measuring an extract at a low concentration

(4.75 g/L) increased ER levels in human MCF-

7 cells as did estradiol (81). An unspecified black cohosh

extract tested in a transient gene expression assay using

HeLa cells co-transfected with an estrogen-dependent reporter

plasmid in the presence of human ER- or ER-

cDNA failed to show transactivation of the gene (82).

Plasma Hormone Levels

The effect of black cohosh on serum concentrations of FSH

and LH has been studied extensively. Crude alcoholic extracts

suppressed plasma LH with no effect on FSH in

ovx rats (75,77). Further fractionation of the crude extract

resulted in activity of the lipophilic fraction while

the hydrophilic fractions were devoid of this activity (74).

A later study in rats using lipophilic and hydrophilic extracts

at high doses (140 and 216 mg/rat, IP) resulted in

LH suppression with a single injection administration of

the lipophilic but not the hydrophilic extract (75). Another

study reported LH suppression in ovx rats with

an unspecified dose of black cohosh extract (83). A recent

study compared the effect of BNO 1055 with that

of estradiol on LH levels (79). Extract administered subcutaneously

at a dosage of 60 mg/day for 7 days was

reported to reduce LH levels in the treated animals. However,

another study reported no estrogen agonistic effects

on FSH, LH, or prolactin levels in ovx rats using the 7,12-

Dimethylbenz(a)anthracene model following 7 weeks of

daily administration of a 40% isopropanolic extract of the

plant (Remifemin) (84).

Hormonal Secretion

The effect of black cohosh on prolactin secretion in pituitary

cell cultures was measured using an unspecified

extract (85). Basal and Thyrotropin-releasing hormone

(TRH)-stimulated prolactin levels were significantly reduced

at doses of 10 and 100 g/mL. This effect was

reversed by the addition of haloperidol (D2-antagonist) to

the cell cultures, suggesting dopaminergic regulation of

hormone secretion by black cohosh.

Osteopenia Inhibition

The black cohosh extract BNO 1055 (60 mg/rat, SC) has

been shown to increase the expression of collagen I and

osteocalcin in rats in a manner similar to that produced

by 8 g of estradiol in ovx rats (79). An additional study

using BNO 1055 demonstrated an osteoprotective effect

as shown by a reduced loss of bone mineral density in

rat tibia after 3 months of administration (81). A study

using an unspecified isopropanol extract of black cohosh

showed reduced urinary markers of bone loss. The authors

64 Fabricant et al.

Table 1 Selected Black Cohosh Clinical Studies

Author (reference no.) Year Extract/formulation/dosage Study length N Outcome measure/result Study design

Kessel Kaul (110) 1957 Remifemin R

60 drops 2 wk 63 Alleviation of climacteric complaints in 95%

of patients

Case series

Schotten (111) 1958 Remifemin 20 drops 3–4 wk 22 Alleviation of neurovegetative and psychic

complaints associated with menopause and

premenopause

Case series

Foldes (53) 1959 Remifemin, 3 tablets/day Unknown 41 31 patients of the verum group responded

to the treatment with a decrease in

menopausal complaints

Placebo,

controlled, open,

crossover, patient

self-assessment

Starfinger (112) 1960 Remifemin, 3–20 drops/day 1 yr 105 Decreased climacteric complaints without

incidence of side effects or resulting in

non physiological bleeding

Case series

Brucker (113) 1960 Remifemin, tablets, variable

dose

Variable 87 (517) Alleviation of menopausal complaints Case series

Heizer (114) 1960 Remifemin, tablets 3–6/day 2–18 mo 66 Alleviation of menopausal (neurovegetative

and psychic) complaints in 47% of patients

with intact uteri and 35% with

hysterectomies

Case series

Gorlich (115) 1962 Remifemin, tablets, variable

dose

Variable 41 (258) Alleviation of climacteric and vascular

symptoms in 85% of patients

Case series

Schildge (116) 1964 Remifemin, fluid extract

60 drops/day

Variable 135 Euphoric and mild sedative-calming effects

in all pts

Case series

Stolze (117) 1982 Remifemin, fluid extract

80 drops/day

6–8 wk 629 Alleviation of neurovegetative and

psychological menopausal symptoms in

80% of patients

Open, physician

and patient

self-assessment

Daiber (118) 1983 Remifemin, fluid extract

80 drops/day

12 wk 36 Alleviation of climacteric complaints (hot

flashes, insomnia, sweating, and

restlessness)

Open, KMI, CGI

Vorberg (119) 1984 Remifemin, fluid extract

80 drops/day

12 wk 50 Significant or highly significant alleviation of

menopausal (neurovegetative and psychic)

complaints; study included subjects

contraindicated to hormone therapy

Randomized,

open, KMI, CGI,

POMS

Warnecke (120) 1985 Remifemin, fluid extract

80 drops/day

12 wk 20 Significant alleviation of symptoms (psychic

and neurovegetative) in the black cohosh,

conjugated estrogen, and diazepam groups.

Vaginal cytology of treatment group was

comparable to estrogenic stimulation

Randomized,

open, KMI, HAM-A,

SDS, CGI,

karyopyknosis

index, eosinophil

index

Stoll (121) 1987 Remifemin, tablets

equivalent to 8 mg

extract/day

12 wk 26 Significant alleviation of climacteric

symptoms (vaginal atrophy, neurovegetative

and psychic complaints) in comparison with

estrogen and placebo groups

Double-blinded,

randomized,

placebo controlled,

KMI,

HAM-A, VMI

(vaginal

epithelium)

Petho (122) 1987 Remifemin, tablets,

unspecified dose

6 mo 50 KMI decreased significantly from 17.6 to

9.2, correlates with a significant reduction

in neurovegetative symptoms. Severity of

subjective self-assessments of subjects

physical and psychological symptoms

decreased

Open, KMI, patient

self-assessment

Lehman-Willenbrock

and Riedel (123)

1988 Remifemin, tablets

equivalent to 8 mg

extract/day

6 mo 15 Significant alleviation of climacteric

symptoms in black cohosh and drug

treatment groups. No significant change in

gonadotropin (FSH, LH) levels

Randomized,

open, KMI

Duker et al. (75) 1991 Remifemin, tablets

equivalent to 40 mg dried

herb/day

2 mo 110 LH suppression In vitro study using

blood from

menopausal

women taking

black cohosh

Black Cohosh 65

Table 1 Selected Black Cohosh Clinical Studies (Continued)

Author (reference no.) Year Extract/formulation/dosage Study length N Outcome measure/result Study design

Baier-Jagodinski

(124)

1995 Cimisan R

T Tropfen,

variable dose

4–8 wk 157 89% of patients showed symptom improvement

after 4 wk. At final visit, the efficacy was assessed

as very good, 40%; good, 41%; sufficient, 12%;

inadequate, 7%

Open, uncontrolled

Mielnik (69) 1997 Uncharacterized extract,

4 mg daily

6 mo 34 Alleviation of climacteric (neurovegetative)

symptoms in 76% of patients after 1 mo

Open, KMI

Georgiev and

Iordanova (70)

1997 Uncharacterized extract,

unspecified dose

3 mo 50 Alleviation of climacteric symptoms in 90% of

patients. Increase in vaginal cell proliferation

(VMI) in 40% of treated women

Open, KMI,

HAM-A, VMI

Nesselhut and Liske

(125)

1999 Remifemin, tablets,

equivalent to 136 mg dried

herb/day

3 mo 28 Good to very good alleviation of 10 menopausal

symptoms in 80% of study participants

Open, postmarket

surveillance

Jacobson, et al. (63) 2001 Remifemin, tablets

equivalent to 40 mg dried

herb/day

60 days 42a No change in median number or intensity of hot

flashes

Double blinded,

randomized,

placebo

controlled, patient

self-assessment,

VAS, MSS

Liske et al. (67) 2002 Unique Cimicifuga

racemosa preparation,

equivalent to 39 or

127.3 mg/day

6 mo 152 No direct systemic estrogenic effect on serum

levels of FSH, LH, SHBG, prolactin, and 17-

estradiol. No change in vaginal cytology. Higher

dose had a more significant reduction in KM

index after 6 mo. Significant reduction with both

doses in neurovegetative and psychic complaints

Drug equivalence

trial, KMI, SDS,

CGI

Hernandez Munoz and

Pluchino (66)

2003 BNO 1055 12 mo 136 Combination therapy with tamoxifen (20 mg)

reduced severity and incidence of hot flashes

Open, randomized,

patient

self-assessment

Wuttke et al. (64) 2003 Klimadynon R

/BNO 1055 3 mo 62 Equipotent to 0.6 CE for relief of climacteric

complaints and for bone resorption. No effect on

endometrial thickness

Randomized,

double blinded,

placebo

controlled,

multicenter, MRS

Verhoeven et al.

(126)

2005 125 mg soy extract daily

(providing 50 mg

isoflavones including 24 mg

genistein and 21.5 mg

daidzein), 1500 mg evening

primrose oil extract

(providing 150 mg gamma

linoleic acid), 100 mg

Actaea racemosa L. extract

(providing 8 mg

deoxyacetein), 200 mg

calcium, 1.25 mg vitamin D,

and 10 IU vitamin E,

placebo group received

2000 mg olive oil daily

12 wk 124 Subjects were experiencing at least five

vasomotor symptoms every 24 hr at study entry.

At weeks 6 and 12, all scores in both groups had

improved compared with baseline, though the

overall difference in scores between the groups

was not statistically significant

Multicenter,

randomized,

placebo controlled,

double-blind

study, Kupperman

index and Greene

Climacteric scale

Nappi et al. (127) 2005 Aqueous isopropanolic

extract 40 mg/day

3 mo 64 Postmenopausal women were recruited. Both CR

and low-dose TTSE2 significantly reduced the

number of hot flushes per day (P < 0.001) and

vasomotor symptoms (P < 0.001), starting at

the first month of treatment. Such a positive

effect was maintained throughout the 3 mo of

observation, without any significant difference

between the two treatments. An identical effect

was evident also for both anxiety (P < 0.001)

and depression (P < 0.001), which were

significantly reduced following 3 mo of both CR

and low-dose TTSE2. Total cholesterol was

unchanged by CR treatment but significantly

(P < 0.033) reduced by 3 mo of low-dose TTSE2.

A slight but significant increase of HDL cholesterol

Randomized,

controlled, clinical

study

(continued)

66 Fabricant et al.

Table 1 Selected Black Cohosh Clinical Studies (Continued)

Author (reference no.) Year Extract/formulation/dosage Study length N Outcome measure/result Study design

(P < 0.04) was found only in women treated with

CR, while LDL-cholesterol levels were significantly

lowered by 3 mo of both CR (P < 0.003) and

low-dose TTSE2 (P < 0.002). Triglyceride levels

were not affected by both treatments nor was liver

function. FSH, LH, and cortisol were not

significantly affected after the 3-mo treatment,

while PRL (P < 0.005) and 17--E2 (P <

0.001) were increased slightly only by low-dose

TTSE2. Endometrial thickness was not affected by

either CR or low-dose TTSE2

Frei-Kleiner et al.

(128)

2005 6.5 mg dry rhizome extract;

60% ethanol extraction

solvent. Dose = 1 cap daily

12 wk 122 Menopausal women were recruited. The primary

efficacy analysis showed no superiority of the

tested black cohosh extract compared with

placebo. However, in the subgroup of patients

with a Kupperman index > or = 20 a significant

superiority regarding this index could be

demonstrated (P < 0.018). A decrease of 47%

and 21% was observed in the black cohosh and

placebo group, respectively. The weekly weighted

scores of hot flashes (P < 0.052) and the

Menopause Rating Scale (P < 0.009) showed

similar results. Prevalence and intensity of the

adverse events did not differ in the two treatment

groups

Multicenter,

randomized,

placebo controlled,

double-blind,

parallel group

study

Pockaj et al. (61) 2006 20 mg C. racemosa and

rhizome extract standardized

to contain 1 mg of triterpene

glycosides as calculated by

27-deoxyacetin, placebo

Two 4-wk

crossover

treatment

periods

132 Toxicity was minimal and not different by

treatment group. Patients receiving black cohosh

reported a mean decrease in hot flash score of

20% (comparing the fourth treatment week with

the baseline week) compared with a 27%

decrease for patients on placebo (P = 0.53).

Mean hot flash frequency was reduced 17% on

black cohosh and 26% on placebo (P = 0.36).

Patient treatment preferences were measured

after completion of both treatment periods by

ascertaining which treatment period, if any, the

patient preferred. Thirty-four percent of patients

preferred the black cohosh treatment, 38%

preferred the placebo, and 28% did not prefer

either treatment

Double-blind,

randomized,

crossover clinical

trial. Primary end

point was the

average

intrapatient hot

flash score (a

construct of

average daily hot

flash severity and

frequency)

difference between

the baseline week

and the last study

week of the first

treatment period.

Green Climacteric

scale

Newton et al. (HALT)

(62)

2006 (i) Black cohosh, 160 mg

daily; (ii) multi botanical with

black cohosh, 200 mg daily,

and 9 other ingredients;

(iii) multi botanical plus

dietary soy counseling;

(iv) conjugated equine

estrogen, 0.625 mg daily,

with or without

medroxyprogesterone

acetate, 2.5 mg daily; or

(v) placebo

1 yr 351 Women aged 45–55 yr with two or more

vasomotor symptoms per day were recruited.

Vasomotor symptoms per day, symptom intensity,

Wiklund Vasomotor Symptom Subscale score did

not differ between the herbal interventions and

placebo at 3, 6, or 12 mo or for the average over

all the follow-up time points (P > 0.05 for all

comparisons) with 1 exception: At 12 mo,

symptom intensity was significantly worse with

the multi botanical plus soy intervention than with

placebo (P > 0.016). The difference in

vasomotor symptoms per day between placebo

and any of the herbal treatments at any time

point was less than one symptom per day; for the

average over all the follow-up time points, the

difference was less than 0.55 symptom per day.

The difference for hormone therapy versus

placebo was −4.06 vasomotor symptoms per day

for the average over all the follow-up time points

(95% CI, −5.93 to −2.19 symptoms per day;

Randomized,

double-blind,

placebo-controlled

trial. Wiklund

Vasomotor

Symptom scale

Black Cohosh 67

Table 1 Selected Black Cohosh Clinical Studies (Continued)

Author (reference no.) Year Extract/formulation/dosage Study length N Outcome measure/result Study design

P > 0.001). Differences between treatment

groups smaller than 1.5 vasomotor

symptoms per day cannot be ruled out.

Black cohosh containing therapies had no

demonstrable effects on lipids, glucose,

insulin, or fibrinogen (124)

Raus et al. (129) 2006 Dried aqueous/ethanolic

(58% vol/vol) extract CR

BNO 1055 of the rhizome of

Actaea or CR (black cohosh)

1 yr 400 Postmenopausal women with symptoms

related to estrogen deficiency were

recruited. The lack of endometrial

proliferation and improvement of climacteric

complaints as well as only a few gynecologic

organ-related adverse events are reported

for the first time after a treatment period of

1 yr

Prospective,

open-label,

multinational,

multicenter study.

Endovaginal

ultrasonography

Sammartino et al.

(130)

2006 Group A (n = 40) was

treated with 1 tablet/day

per os containing a

combination of isoflavones

[soy germ extracts, Glycine

max, no OGM-SoyLife:

150 mg, titrated in

isoflavones (40%) =

60 mg], lignans [flaxseed

extracts, Linum

usitatissimum, no

OGM-LinumLife: 100 mg,

titrated in lignans (20%) =

20 mg] and C. racemosa

[50 mg, titrated in

triterpene (2.5%) =

1.25 mg] (Euclim R

; Alfa

Wassermann, Italy); group B

(n = 40) was treated with

calcium supplements

(Metocal, Rottapharm,

Monza, Italy)

Three cycles

of 28 days

80 Healthy postmenopausal women were

recruited. At baseline no significant

difference was detected in KI between

groups A and B; however, after three cycles

of treatment, KI was significantly (P >

0.05) lower in group A compared with

baseline and with group B

Double-blind,

randomized,

placebo-controlled

trial, Kupperman

index

Gurley et al. (131) 2006 Milk thistle (300 mg, three

times daily, standardized to

contain 80% silymarin),

black cohosh extract

(20 mg, twice daily,

standardized to 2.5%

triterpene glycosides),

rifampin (300 mg, twice

daily), and clarithromycin

(500 mg, twice daily)

14 days 16 Young adults (8 females) (age, mean °æ

SD = 26 °æ 5 yr; weight, 75 °æ 13 kg)

compared with the effects of rifampin and

clarithromycin, the botanical supplements

milk thistle and black cohosh produced no

significant changes in the disposition of

digoxin, a clinically recognized P-gp

substrate with a narrow therapeutic index.

Accordingly, these two supplements appear

to pose no clinically significant risk for

P-gp-mediated herb–drug interactions

Randomized

controlled, clinical

pharmacokinetic

trial

Rebbeck et al. (132) 2007 Varied Case-control

design

949

breast

cancer

cases;

1524

controls

HRS varied significantly by race, with African

American women being more likely than

European American women to use any

herbal preparation (19.2% vs. 14.7%, P =

0.003) as well as specific preparations

including black cohosh (5.4% vs. 2.0%,

P > 0.003), ginseng (12.5% vs. 7.9%,

P < 0.001) and red clover (4.7% vs. 0.6%,

P < 0.001). Use of black cohosh had a

significant breast cancer protective effect

(adjusted odds ratio 0.39, 95% CI:

0.22–0.70). This association was similar

among women who reported use of either

black cohosh or Remifemin (a herbal

preparation derived from black cohosh;

adjusted odds ratio 0.47, 95% CI:

0.27–0.82)

Population-based

case–control study

(continued)

68 Fabricant et al.

Table 1 Selected Black Cohosh Clinical Studies (Continued)

Author (reference no.) Year Extract/formulation/dosage Study length N Outcome measure/result Study design

Hirschberg et al.

(133)

2007 Remifemin (batch no.

229690), one tablet twice

daily. Each tablet contains

0.018–0.026 mL liquid

extract of black cohosh

rootstock (0.78–1.14:1)

corresponding to 20 mg

herbal drug [i.e., 2.5 mg dry

extract, extraction agent

isopropanol 40% (vol/vol)],

40 mg/day

6 mo 74 None of the women showed any increase

in mammographic breast density.

Furthermore, there was no increase in

breast cell proliferation. The mean change

°æ SD in proportion of Ki-67-positive cells

was 0.5% °æ 2.4% (median, 0.0; 95%

CI=−1.32–0.34) for paired samples.

The mean change in endometrial thickness

°æ SD was 0.0 °æ 0.9 mm (median, 0.0). A

modest number of adverse events were

possibly related to treatment, but none of

these were serious. Laboratory findings

and vital signs were normal

Prospective, open,

uncontrolled drug

safety study

Chung et al. (71) 2007 Gynoplus (264 mg tablet

with 0.0364 mL Cimicifuga

racemosa rhizome,

equivalent to 1 mg terpene

glycosides; 84 mg dried

Hypericum perforatum

extract, equivalent to 0.25

mg hypericin, with 80%

methanol)

12 wk 89 Kupperman index (KI) for climacteric

complaints. Vaginal maturation indices,

serum estradiol, FSH, LH, total cholesterol,

HDL-cholesterol, LDL-cholesterol, and

triglyceride levels. Significant

improvements in climacteric symptoms

and hot flashes, as well as an increase in

HDL (from 58.32 °æ 11.64 to 59.74 °æ

10.54) were observed in the Gynoplus

group by 4 wk and maintained after 12 wk,

compared with the placebo group. There

was no significant impact on superficial

cell proportion

Randomized,

double-blind,

placebo-controlled

trial

Ruhlen et al. (22) 2007 Remifemin R and CimiPure

(2.5% triterpenes; 40 mg

capsule contains 1 mg

23-epi-26-deoxyactein)

12 wk

followed by

12 wk

washout

61 Subjects experienced relief of menopausal

symptoms, with reversion to baseline after

washout. No effect on serum estrogenic

markers. No effect on pS2 or cell

morphology in nipple aspirate

Open study

Gurley et al. (134) 2008 Milk thistle (300 mg, three

times daily, standardized to

contain 80% silymarin),

black cohosh extract

(40 mg, twice daily,

standardized to 2.5%

triterpene glycosides),

rifampin (300 mg, twice

daily), and clarithromycin

(500 mg, twice daily)

14 days 19 Young adults [9 women; age (mean °æ SD)

= 28 °æ 6 yr; weight = 76.5 °æ 16.4 kg].

Milk thistle and black cohosh appear to

have no clinically relevant effect on CYP3A

activity in vivo. Neither spontaneous

reports from study participants nor their

responses to questions asked by study

nurses regarding supplement/medication

usage revealed any serious adverse events

Randomized

controlled, clinical

pharmacokinetic

trial

Amsterdam et al. (73) 2009 12 wk 28 (15

treatment/

13

placebo)

The primary outcome measure was

changed over time in total HAM-A scores.

Secondary outcomes included a change in

scores on the Beck Anxiety Inventory,

Green Climacteric Scale (GCS), and

Psychological General Well-Being Index

(PGWBI) and the proportion of patients

with a change of 50% or higher in baseline

HAM-A scores. There was neither a

significant group difference in change over

time in total HAM-A scores (P = 0.294)

nor a group difference in the proportion of

subjects with a reduction of 50% or higher

in baseline HAM-A scores at study end

point (P = 0.79). There was a significantly

greater reduction in the total GCS scores

during placebo (vs. black cohosh; P =

0.035) but no group difference in change

over time in the GCS subscale scores or in

the PGWBI (P = 0.140). One subject

(3.6%) taking black cohosh discontinued

treatment because of adverse events

Randomized,

double-blind,

placebo-controlled

trial

Black Cohosh 69

Table 1 Selected Black Cohosh Clinical Studies (Continued)

Author (reference no.) Year Extract/formulation/dosage Study length N Outcome measure/result Study design

Geller et al. (72) 2009 12 mo 89 Primary outcome measures were reduction

in vasomotor symptoms (hot flashes and

night sweats) by black cohosh and red

clover compared with placebo; secondary

outcomes included safety evaluation,

reduction of somatic symptoms, relief of

sexual dysfunction, and overall improvement

in quality of life. Reductions in number of

vasomotor symptoms after a 12-mo

intervention were as follows: black cohosh

(34%), red clover (57%), placebo (63%),

and CEE/MPA (94%), with only CEE/MPA

differing significantly from placebo. Black

cohosh and red clover did not significantly

reduce the frequency of vasomotor

symptoms as compared with placebo.

Secondary measures indicated that both

botanicals were safe as administered. In

general, there were no improvements in

other menopausal symptoms

Randomized,

double-blind,

placebo-controlled

trial

Studies listed by year of publication.

aAll with breast cancer history.

Abbreviations: CGI, Clinician’s Global Impression scale; HAM-A, Hamilton Anxiety scale; KMI, Kupperman Menopausal Index; MSS, unspecified menopausal index

using the Likert scale; Open, open-labeled; POMS, Profile of Mood States Scale; SDS, Self-Assessment Depression scale; VAS, Visual Analog Scale; VMI, Vaginal

Maturity Index.

of this study suggested the action was similar to that of the

SERM Raloxifene (86).Afollow-up study using BNO 1055

versus CE therapy showed beneficial effects of the extract

on bone metabolism in humans, specifically an increase in

bone-specific alkaline phosphatase in serum(64). While no

direct correlation between species has been established, it

is of note that studies of Asian Cimicifuga species have

demonstrated similar activity and may be of importance

for further investigation of this biological activity (87,88).

Uterine Weight/Estrous Induction

Uterine and ovarian weight increase, cell cornification,

and an increased duration of estrous are generally considered

evidence of endometrial estrogenic activity. However,

it has recently been proposed that uterine weight

is a poor marker for endometrial effects (89). Three studies

demonstrating that black cohosh extracts increased the

uterine weight of ovx rats have been reported (50,77,90)

with two of the studies using an undescribed root extract

(77,90). One study on immature mice reported similar

findings (50). By contrast, two studies on ovx rats

(79,91), as well as four studies on immature mice, reported

the converse (79,81,83,92). One of these studies

found that although there was no increase in uterine or

ovarian weight, the duration of estrous was significantly

increased by black cohosh (92). A subsequent study by the

authors and collaborators demonstrated no attenuation

in uterine weight at variable doses (4, 40, and 400 mg/

kg/day) of a 40% isopropanol extract in ovx rats (4).

Cell Proliferation

An unspecified black cohosh extract failed to significantly

induce growth of MCF-7 cells when compared with untreated

control cells (81). A study using isopropanolic and

ethanolic extracts also failed to induce growth of MCF-7

cells (93).

CNS Effects and Neurotransmitter Binding

A murine study using an unspecified extract (25–100

mg/kg, orally) measured effects on body temperature and

ketamine-induced sleep time using bromocriptine (D2-

agonist) as a positive control. Pretreatment with sulpiride

(D2 blocker) suggested a receptor-mediated dopaminergic

effect (84). An additional mouse study was carried

out to characterize neurotransmitter levels in the striatum

and hippocampus after pretreatment with the extract

for 21 days (94). Serotonin and dopamine metabolic levels

in the striatum were substantially lower in comparison

with the control group. These studies have led to

the hypothesis that dopaminergic, rather than estrogenic,

activity is responsible for the reported success of black cohosh

in reducing climacteric symptoms (95,96). A study

by the authors and collaborators has pointed to the effects

of black cohosh being mediated by serotonin (5-HT)

receptors (4). Three different extracts (100% methanol,

40% isopropanol, 75% ethanol) were found to bind to the

5-HT7-receptor subtype at IC50 ≤ 3.12 g/mL. The 40%

isopropanol extract inhibited (3H)-lysergic acid diethylamide

binding to the 5-HT7 receptor with greater potency

than (3H)-8-hydroxy-2(di-N-propylamino)tetralin to the

rat 5-HT1A. Analysis of ligand-binding data suggests that

the methanol extract functioned as a mixed competitive

ligand of the 5HT7 receptor. Further testing of the

methanol extract in 293T-5-HT7 transfected HEK cells

raised cAMP levels; these raised levels were reversed in

the presence of the 5-HT antagonist methiothepin, indicating

a receptor-mediated process and possible agonist

activity local to the receptor (4).

70 Fabricant et al.

Antioxidant

A black cohosh methanol extract protected S30 breast cancer

cells against menadione-inducedDNAdamage at variable

concentrations and scavenged DPPH free radicals at

a concentration of 99 M (38).

USE IN PREGNANT/LACTATING WOMEN

Despite an absence of mutagenic effects reported to date,

the use of black cohosh during pregnancy is contraindicated

according toWHOsuggestions (97). Data are inconclusive

regarding the effects on lactation.

DOSAGE (97,98)

Recommended doses for black cohosh are as follows:

1. Dried rhizome and root: 1 g up to three times daily.

2. Tincture (1:10): 0.4 mL daily (40–60% alcohol vol/vol).

3. Fluid extract (1:1): 20 drops twice daily (60% ethanol

vol/vol, equivalent to 40 mg dried herb).

4. Tablet equivalence: two tablets a day (equivalent to

40 mg dried extract).

The Commission E monograph also recommends

that usage not be extended for more than 6 months due to

a lack of long-term safety data. Experimental data are not

available to suggest this 6-month limit.

ADVERSE EFFECTS SAFETY

A majority of adverse event reports (AERs) for black

cohosh have been associated with Remifemin products,

probably due to its widespread use. Thus, the AER data

may speak more to the safety of this particular product

rather than black cohosh extracts in general. In clinical

trials, minor cases of nausea, vomiting, dizziness, and

headaches have been reported (61–73). An analysis of the

safety data from published clinical trials, case studies,

postmarketing surveillance studies, spontaneous report

programs, and phase I studies was carried out (99). The

data obtained from more than 20 studies, including more

than 2000 patients, suggest that adverse event occurrence

with black cohosh is rare, and that such events are mild

and reversible, the most common being gastrointestinal

upset and rashes. The same review investigated black cohosh

preparation and AERs and concluded that adverse

events are rare, mild, and reversible (99).

That said, black cohosh has garnered a great deal of

attention with respect to its safety over the past 5 years,

with the emergence of a few case reports citing acute hepatitis,

convulsions, cardiovascular, and circulatory insult

(100–104). It is important to note that in a number of

these reports, no effort was made to positively identify

the botanical associated with the event as black cohosh.

In one case, depositions taken during a legal proceeding

revealed that the lack of alcohol consumption and concomitant

medications reported in a published case report

(101) was inaccurate (105). Underreporting of adverse effects

may also be a common problem with botanical supplement

(100–104). However, these case reports have generated

much interest within the research community, so

much so that two workshops have been convened by the

National Institutes of Health (NIH) on the specific issue

of the safety of black cohosh preparations: one workshop

sponsored by the National Center for Complementary and

Alternative Medicine (NCCAM) and the Office of Dietary

Supplements (ODS) in November 2004 and a more recent

workshop sponsored by the ODS held in June 2007. The

report from the 2004 workshop indicated that there is “no

plausible mechanism of liver toxicity.” The 2007 workshop

offered no conclusions on safety to contradict those

of the 2004 meeting regarding hepatotoxicity of black cohosh

preparations. The 2007 workshop did recommend

that active steps be taken to monitor liver health in human

clinical trials of black cohosh (106).

It is also noteworthy that in the 2004 workshop, it

was agreed that “suspected hepatotoxicity should not be

broadcast when toxicity has not been demonstrated.” Despite

concerns by some scientists, a warning statement on

commercial black cohosh product labels was mandated

in Australia by the Therapeutic Goods Administration

(TGA), and the European Medicines Agency (EMEA) released

a press statement on July 18, 2006, urging patients

to stop taking black cohosh if they develop signs suggestive

of liver injury. It is noteworthy that it is not clear and

has never been fully disclosed as to how these agencies

reached their decision and what the scientific data were

that led to these warning statements.

While the notion of idiosyncratic hepatotoxicity was

raised in the June 2007 workshop by toxicologists from the

Food and Drug Administration (FDA), it was acknowledged

by these toxicologists that without data from a

mandatory adverse event reporting system, no real conclusion

on causality regarding idiosyncratic hepatotoxicity

can be drawn from case reports.

In the September–October 2007 edition of USP’s

Pharmacopeial Forum (100), the USP proposed the addition

of a cautionary statement for USP quality black

cohosh products with regard to liver toxicity. The American

Botanical Council (ABC) responded that given the

long history of safe black cohosh use and the lack of clear

scientific evidence for toxicity, there is not enough information

for such a warning. The ABC noted that of the 42

case reports of toxicity cited by the USP, only 18 met criteria

for assessment based on a standard-rating scale, and

of these, 3 met criteria for “possible” toxicity, and 2 for

“probable” toxicity. Many case reports were also said to

lack adequate documentation regarding the actual identity

of the black cohosh used and possible confounding

factors (107).

 

COMPENDIAL REGULATORY STATUS

Black cohosh products are regulated and marketed in the

United States as dietary supplements under the provisions

of the Dietary Supplement Health and Education

Act (DSHEA) of 1994 (U.S.C. § 321). Dried black cohosh

rhizome and roots, powdered black cohosh, black cohosh

fluid extract, powdered black cohosh extract, and black

cohosh tablets now have official standing in dietary supplement

monographs in the United States Pharmacopoeia-–

National Formulary (108). In the European Union nations,

Black Cohosh 71

black cohosh products are approved as nonprescription

phytomedicines when administered orally in compliance

with the German Commission E monographs (109).

 

CONCLUSIONS

With the elevated concern surrounding side effects

related to classical hormone/estrogen therapy for

menopause, modulation of certain climacteric symptoms

of menopause by both dopaminergic and serotonergic

drugs is becoming a more viable and frequent treatment

option. A review of the clinical trials associated with black

cohosh leads to the conclusion that women using hydroalcoholic

extracts of the rhizomes and roots of this plant may

gain relief from climacteric symptoms (i.e., hot flashes)

in comparison with placebo over the short term, whereas

longer studies have not shown the same degree of efficacy.

Further clouding the review of these clinical trials is the

wide variety and different types of extracts administered

in published studies. Early in vitro studies reported that

black cohosh extracts acted on ERs or had a sort direct

effect on ERs. Now it is becoming clear that the beneficial

effect of reducing hot flashes is related, at least in

part, to serotonergic or dopaminergic mechanisms that

regulate hypothalamic control and possibly mediate estrogenic

mechanisms. As mentioned earlier, the controversy

surrounding a purported direct estrogenic mechanism of

action may also be due to variance in the extracts assayed.

Overall, given variation in trial length, extract types, and

other potential confounders, the efficacy of black cohosh

as a treatment for menopausal symptoms is uncertain and

further rigorous trials seem warranted.

 

REFERENCES

1. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in

breast-cancer incidence in 2003 in the United States. N Engl

J Med 2007; 356(16):1670–1674.

2. Nelson HD,Humphrey LL, Nygren P, et al. Postmenopausal

hormone replacement therapy: scientific review. JAMA

2002; 288(7):872–881.

3. Rhyu MR, Lu J,Webster DE, et al. Black cohosh (Actaea racemosa,

Cimicifuga racemosa) behaves as a mixed competitive

ligand and partial agonist at the human mu opiate receptor.

J Agric Food Chem 2006; 54(26):9852–9857.

4. 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(19):5661–5670.

5. Farnsworth NR. NAPRALERT Database. Chicago, IL: University

of Illinois at Chicago, 2003. http://www.napralert

.org. Accessed May 3, 2010.

6. Chen SN, Lankin DC, Nikolic D, et al. Chlorination diversifies

Cimicifuga racemosa triterpene glycosides. J Nat Prod

2007; 70(6):1016–1023.

7. Qiu SX, Dan C, Ding LS, et al. A triterpene glycoside from

black cohosh that inhibits osteoclastogenesis by modulating

RANKL and TNF-alpha signaling pathways. Chem Biol

2007; 14(7):860–869.

8. Jiang B, Kronenberg F, Nuntanakorn P, et al. Evaluation

of the botanical authenticity and phytochemical profile

of black cohosh products by high-performance liquid

chromatography with selected ion monitoring liquid

chromatography-mass spectrometry. J Agric Food Chem

2006; 54(9):3242–3253.

9. He K, Pauli GF, Zheng B, et al. Cimicifuga species identification

by high performance liquid chromatographyphotodiode

array/mass spectrometric/evaporative light

scattering detection for quality control of black cohosh

products. J Chromatogr A 2006; 1112(1–2):241–254.

10. Lai GF,Wang YF, Fan LM, et al. Triterpenoid glycoside from

Cimicifuga racemosa. J Asian Nat Prod Res 2005; 7(5):695–699.

11. Chen SN, LiW, Fabricant DS, et al. Isolation, structure elucidation,

and absolute configuration of 26-deoxyactein from

Cimicifuga racemosa and clarification of nomenclature associated

with 27-deoxyactein. J Nat Prod 2002; 65(4):601–605.

12. Wang HK, Sakurai N, Shih CY, et al. LC/TIS-MS fingerprint

profiling of Cimicifuga species and analysis of 23-epi-26-

deoxyactein in Cimicifuga racemosa commercial products. J

Agric Food Chem 2005; 53(5):1379–1386.

13. van Breemen RB, Liang W, Banuvar S, et al. Pharmacokinetics

of 23-epi-26-deoxyactein in women after oral administration

of a standardized extract of black cohosh. Clin

Pharmacol Ther 2010; 87(2):219–225.

14. Sun LR, Qing C, Zhang YL, et al. Cimicifoetisides A and B,

two cytotoxic cycloartane triterpenoid glycosides from the

rhizomes of Cimicifuga foetida, inhibit proliferation of cancer

cells. Beilstein J Org Chem 2007; 3:3.

15. Li JX, Yu ZY. Cimicifugae rhizoma: from origins, bioactive

constituents to clinical outcomes. Curr Med Chem 2006;

13(24):2927–2951.

16. Tian Z, Pan RL, Si J, et al. Cytotoxicity of cycloartane triterpenoids

from aerial part of Cimicifuga foetida. Fitoterapia

2006; 77(1):39–42.

17. Tsukamoto S, Aburatani M, Ohta T. Isolation of CYP3A4

inhibitors from the black cohosh (Cimicifuga racemosa). Evid

Based Complement Alternat Med 2005; 2(2):223–226.

18. Onorato J, Henion JD. Evaluation of triterpene glycoside

estrogenic activity using LC/MS and immunoaffinity extraction.

Anal Chem 2001; 73(19):4704–4710.

19. Stute P, Nisslein T, G¨ otte M, et al. Effects of black cohosh

on estrogen biosynthesis in normal breast tissue in vitro.

Maturitas 2007; 57(4):382–391.

20. Kretzschmar G, Nisslein T, Zierau O, et al. No estrogen-like

effects of an isopropanolic extract of rhizoma Cimicifugae

racemosae on uterus and vena cava of rats after 17 day treatment.

J Steroid Biochem Mol Biol 2005; 97(3):271–277.

21. 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(5):2472–2479.

22. Ruhlen RL, Haubner J, Tracy JK, et al. Black cohosh does not

exert an estrogenic effect on the breast. Nutr Cancer 2007;

59(2):269–277.

23. Gaube F, Wolfl S, Pusch L, et al. Gene expression profiling

reveals effects of Cimicifuga racemosa (L.) NUTT. (black cohosh)

on the estrogen receptor positive human breast cancer

cell line MCF-7. BMC Pharmacol 2007; 7(1):11.

24. Li W, Sun Y, Liang W, et al. Identification of caffeic acid

derivatives in Actaea racemosa (Cimicifuga racemosa, black cohosh)

by liquid chromatography/tandem mass spectrometry.

Rapid Commun Mass Spectrom 2003; 17(9):978–982.

25. Nuntanakorn P, Jiang B, Einbond LS, et al. Polyphenolic

constituents of Actaea racemosa. J Nat Prod 2006; 69(3):314–

318.

26. Hostanska K, Nisslein T, Freudenstein J, et al. Evaluation

of cell death caused by triterpene glycosides and phenolic

substances from Cimicifuga racemosa extract in human MCF-

7 breast cancer cells. Biol Pharm Bull 2004; 27(12):1970–1975.

27. Gumbinger HG,WinterhoffH, Sourgens H, et al. Formation

of compounds with antigonadotropic activity from inactive

phenolic precursors. Contraception 1981; 23(6):661–666.

28. Winterhoff H, Gumbinger HG, Sourgens H. On the antigonadotropic

activity of Lithospermum and Lycopus species

72 Fabricant et al.

and some of their phenolic constituents. Planta Med 1988;

54(2):101–106.

29. Andary C. Caffeic acid glucoside esters and their pharmacology.

In: Scalbert A, ed. Polyphenolic Phenomena. Paris:

INRA Editions, 1993:237–245.

30. Ortiz de Urbina JJ, Martin ML, Sevilla MA, et al. Antispasmodic

activity on rat smooth muscle of polyphenol compounds

caffeic and protocatechic acids. Phytother Res 1990;

4(2):71–76.

31. Trute A, Gross J, Mutschler E, et al. In vitro antispasmodic

compounds of the dry extract obtained from Hedera helix.

Planta Med 1997; 63(2):125–129.

32. Saturnino PC, Saturnino A, De Martino C, et al. Flavonol

glycosides from Aristeguietia discolor and their inhibitory

activity on electrically-stimulated guinea pig ileum. Int J

Pharmacogn 1997; 35(5):305–312.

33. Okamoto R, Sakamoto S, Noguchi K. Effects of ferulic acid

on FSH, LH and prolactin levels in serum and pituitary tissue

of male rats (author’s transl). Nippon Naibunpi Gakkai

Zasshi 1976; 52(9):953–958.

34. de Man E, Peeke HV. Dietary ferulic acid, biochanin A,

and the inhibition of reproductive behavior in Japanese

quail (Coturnix coturnix). Pharmacol Biochem Behav 1982;

17(3):405–411.

35. Gorewit RC. Pituitary and thyroid hormone responses of

heifers after ferulic acid administration. J Dairy Sci 1983;

66(3):624–629.

36. Ozaki Y, Ma JP. Inhibitory effects of tetramethylpyrazine

and ferulic acid on spontaneous movement of rat uterus in

situ. Chem Pharm Bull (Tokyo) 1990; 38(6):1620–1623.

37. Kruse SO, L¨ohning A, Pauli GF, et al. Fukiic and piscidic

acid esters from the rhizome of Cimicifuga racemosa and the

in vitro estrogenic activity of fukinolic acid. Planta Med

1999; 65(8):763–764.

38. Stromeier S, Petereit F, Nahrstedt A. Phenolic esters from

the rhizomes of Cimicifuga racemosa do not cause proliferation

effects in MCF-7 cells. Planta Med 2005; 71(6):495–

500.

39. Burdette JE, Chen SN, Lu ZZ, et al. Black cohosh (Cimicifuga

racemosa L.) protects against menadione-induced DNA

damage through scavenging of reactive oxygen species:

bioassay-directed isolation and characterization of active

principles. J Agric Food Chem 2002; 50(24):7022–7028.

40. Fabricant DS, Nikolic D, Lankin DC, et al. Cimipronidine,

a cyclic guanidine alkaloid from Cimicifuga racemosa. J Nat

Prod 2005; 68(8):1266–1270.

41. G¨odecke T, Lankin DC, Nikolic D, et al. Guanidine alkaloids

and Pictet–Spengler adducts from black cohosh (Cimicifuga

racemosa) (dagger). J Nat Prod 2009; 72(3):433–437.

42. G¨odecke T, Nikolic D, Lankin DC, et al. Phytochemistry

of cimicifugic acids and associated bases in Cimicifuga

racemosa root extracts. Phytochem Anal 2009; 20(2):120–

133.

43. Dan C, Zhou Y, Ye D, et al. Cimicifugadine from Cimicifuga

foetida, a new class of triterpene alkaloids with novel reactivity.

Org Lett 2007; 9(9):1813–1816.

44. Kusano G. Studies on the constituents of Cimicifuga species.

Yakugaku Zasshi 2001; 121(7):497–521.

45. Struck D, Tegtmeier M, Harnischfeger G. Flavones in extracts

of C. racemosa. Planta Med 1997; 63:289.

46. Panossian A, Danielyan A, Mamikonyan G, et al. Methods

of phytochemical standardisation of rhizoma Cimicifugae

racemosae. Phytochem Anal 2004; 15(2):100–108.

47. Kennelly EJ, Baggett S, Nuntanakorn P, et al. Analysis of

thirteen populations of black cohosh for formononetin. Phytomedicine

2002; 9(5):461–467.

48. Fabricant D, Li W, Chen SN, et al. Geographical and diurnal

variation of chemical constituents of Cimicifuga racemosa

(L.) Nutt. In: Botanical Dietary Supplements: Natural Products

at a Crossroad. Asilomar, CA: American Society of Pharmacognosy,

2001:34.

49. Jiang B, Kronenberg F, Balick MJ, et al. Analysis of

formononetin from black cohosh (Actaea racemosa). Phytomedicine

2006; 13(7):477–486.

50. Ramsey GW. A comparison of vegetative characteristics of

several genera with those of the genus Cimicfuga (Ranunculaceae).

SIDA 1988; 13(1):57–63.

51. Ramsey GW. Morphological considerations in the North

American Cimicifuga (Ranunculaceae). Castanea 1987;

52(2):129–141.

52. Youngken H. A Textbook of Pharmacognosy. 4th ed. Vol.

xiv. Philadelphia, PA: P. Blakiston’s son and Co, 1936:924.

53. Foldes J. The actions of an extract of C. racemosa. Arzneimittelforschung

1959; 13:623–624.

54. Nutrition Business Journal, Global Supplement&Nutrition

Industry Report 2007, 2008:381. http://nutritionbusiness

journal.com/nutrition-industry/market-research/global

supplement nutrition industry report 2007/. Accessed

May 3, 2010.

55. Swanson CA. Suggested guidelines for articles about botanical

dietary supplements. Am J Clin Nutr 2002; 75(1):

8–10.

56. Gagnier J, Boon H, Rochon P, et al. Improving the quality of

reporting of randomized controlled trials evaluating herbal

interventions: implementing the CONSORT statement (corrected).

Explore (NY) 2006; 2(2):143–149.

57. Gagnier JJ, Boon H, Rochon P, et al. Recommendations for

reporting randomized controlled trials of herbal interventions:

explanation and elaboration. J Clin Epidemiol 2006;

59(11):1134–1149.

58. Gagnier JJ, Boon H, Rochon P, et al. Reporting randomized,

controlled trials of herbal interventions: an elaborated

CONSORT statement. Ann Intern Med 2006; 144(5):364–

367.

59. Mills EJ, Wu P, Gagnier J, et al. The quality of randomized

trial reporting in leading medical journals since the revised

CONSORT statement. Contemp Clin Trials 2005; 26(4):480–

487.

60. Nelson HD, Haney E, Humphrey L, et al. Management

of Menopause-Related Symptoms, 2005. http://www.ahrq

.gov/clinic/epcsums/menosum.htm. Accessed May 3,

2010.

61. Pockaj BA, Gallagher JG, Loprinzi CL, et al. Phase III

double-blind, randomized, placebo-controlled crossover

trial of black cohosh in the management of hot flashes: NCCTG

Trial N01CC1. J Clin Oncol 2006; 24(18):2836–2841.

62. Newton KM, Reed SD, LaCroix AZ, et al. Treatment of vasomotor

symptoms of menopause with black cohosh, multibotanicals,

soy, hormone therapy, or placebo: a randomized

trial. Ann Intern Med. 2006; 145(12):869–879.

63. 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(10):2739–2745.

64. 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–S77.

65. Stoll W. Phytopharmacon influences atrophic vaginal epithelium:

double-blind study—Cimicifuga vs. estrogenic

substances. Therapeuticum 1987; 1:23–31.

66. HernandezMunozG, Pluchino S. Cimicifuga racemosa for the

treatment of hot flushes in women surviving breast cancer.

Maturitas 2003; 44(suppl 1):S59–S65.

67. Liske E, H¨anggi W, Henneicke-von Zepelin HH, et al.

Physiological investigation of a unique extract of

black cohosh (Cimicifugae racemosae rhizoma): a 6-month

Black Cohosh 73

clinical study demonstrates no systemic estrogenic effect.

J Womens Health Gend Based Med 2002; 11(2):163–

174.

68. Russell L, Hicks GS, Low AK, et al. Phytoestrogens: a viable

option? Am J Med Sci 2002; 324(4):185–188.

69. Mielnik J. Cimicifuga racemosa in the treatment of neuro vegetative

symptoms in women in the perimenopausal period.

Maturitas 1997; 27(suppl):215.

70. Georgiev DB, Iordanova E. Phytoestrogens—the alternative

approach (abstract). Maturitas 1997; 27(suppl):P309.

71. Chung DJ, Kim HY, Park KH, et al. Black cohosh and St.

John’s wort (GYNO-Plus) for climacteric symptoms. Yonsei

Med J 2007; 48(2):289–294.

72. Geller SE, Shulman LP, van Breemen RB, et al. Safety and

efficacy of black cohosh and red clover for the management

of vasomotor symptoms: a randomized controlled

trial. Menopause 2009; 16(6):1156–11566.

73. Amsterdam JD, Yao Y, Mao JJ, et al. Randomized, doubleblind,

placebo-controlled trial of Cimicifuga racemosa (black

cohosh) inwomenwith anxiety disorder due to menopause.

J Clin Psychopharmacol 2009; 29(5):478–483.

74. Jarry H, Harnischfeger G, Duker E. The endocrine effects

of constituents of Cimicifuga racemosa. 2. In vitro binding of

constituents to estrogen receptors. PlantaMed1985; (4):316–

319.

75. D¨ uker EM, Kopanski L, Jarry H, et al. Effects of extracts

from Cimicifuga racemosa on gonadotropin release in

menopausal women and ovariectomized rats. Planta Med

1991; 57(5):420–424.

76. Jarry H, Harnischfeger G. Endocrine effects of constituents

of Cimicifuga racemosa. 1. The effect on serum levels of

pituitary hormones in ovariectomized rats. Planta Med

1985(1):46–49.

77. Eagon CL, Elm MS, Eagon PK. Estrogenicity of traditional

Chinese andWestern herbal remedies. ProcAmAssoc Cancer

Res 1996; 37:284.

78. Zava DT, Dollbaum CM, Blen M. Estrogen and progestin

bioactivity of foods, herbs, and spices. Proc Soc Exp Biol

Med 1998; 217(3):369–378.

79. Jarry H, Metten M, Spengler B, et al. In vitro effects of

the Cimicifuga racemosa extract BNO 1055. Maturitas 2003;

44(suppl 1):S31–S38.

80. Liu ZP, Yu B, Huo JS, et al. Estrogenic effects of Cimicifuga

racemosa (black cohosh) in mice and on estrogen receptors

in MCF-7 cells. J Med Food 2001; 4(3):171–178.

81. Jarry H, Leonhardt S, Duls C, et al. Organ specific effects

of C. racemosa in brain and uterus. In: 23rd International

LOF-Symposium on Phyto-Oestrogens. Belgium, 1999.

82. Amato P, Christophe S, Mellon PL. Estrogenic activity of

herbs commonly used as remedies for menopausal symptoms.

Menopause 2002; 9(2):145–150.

83. Eagon PK, Tress NB, Ayer HA, et al. Medicinal botanicals

with hormonal activity. Proc Am Assoc Cancer Res 1999;

40:161–162.

84. 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(12):3448–3452.

85. Lohning A, Verspohl E, Winterhoff H. Pharmacological

studies on the dopaminergic activity of C. racemosa.

In: 23rd International LOF-Symposium on “Phyto-

Oestrogens”. Belgium, 1999.

86. Seidlov´a-Wuttke D, Jarry H, Becker T, et al. Pharmacology

of Cimicifuga racemosa extract BNO 1055 in rats: bone, fat

and uterus. Maturitas 2003; 44(suppl 1):S39–S50.

87. Nisslein T, Freudenstein J. Effects of black cohosh on urinary

bone markers and femoral density in an ovx-rat model.

In:World Congress on Osteoporosis. Chicago, IL, 2000. Abstract

504.

88. Li JX, Kadota S, Li HY, et al. Effects of Cimicifugae rhizoma

on serum calcium and phosphate levels in low calcium dietary

rats and bone mineral density in ovariectomized rats.

Phytomedicine 1997; 3(4):379–385.

89. Li JX, Kadota S, Li HY, et al. The effect of traditional

medicines on bone resorption induced by parathyroid hormone

(PTH) in tissue culture: a detailed study on cimicifuga

rhizome. J Trad Med 1996; 13:50–58.

90. Johnson EB, Muto MG, Yanushpolsky EH, et al. Phytoestrogen

supplementation and endometrial cancer. Obstet

Gynecol 2001; 98(5, pt 2):947–950.

91. Eagon CL, Elm MS, Teepe AG, et al. Medicinal botanicals:

estrogenicity in rat uterus and liver. Proc Am Assoc Cancer

Res 1997; 38:293.

92. Einer-Jensen N, Zhao J, Andersen KP, et al. Cimicifuga and

Melbrosia lack oestrogenic effects in mice and rats. Maturitas

1996; 25(2):149–153.

93. Liu Z, Yang Z, Zhu M, et al. Estrogenicity of black cohosh

(Cimicifuga racemosa) and its effect on estrogen receptor level

in human breast cancer MCF-7 cells.Wei ShengYan Jiu 2001;

30(2):77–80.

94. Zierau O, Bodinet C, Kolba S, et al. Antiestrogenic activities

of Cimicifuga racemosa extracts. J Steroid Biochem Mol Biol

2002; 80(1):125–130.

95. Lohning A,WinterhoffH. Neurotransmitter concentrations

after three weeks treatment with Cimicifuga racemosa (abstract).

Phytomedicine 2000; 7(suppl 2):13.

96. Borrelli F, Izzo AA, Ernst E. Pharmacological effects of Cimicifuga

racemosa. Life Sci 2003; 73(10):1215–1229.

97. Mahady GB, Fong HHS, Farnsworth NR. Botanical Dietary

Supplements: Quality, Safety and Efficacy. Lisse, The

Netherlands: Swets & Zeitlinger, 2001:350.

98. Black Cohosh. Standards of analysis, quality control and

therapeutics. In: Upton R, ed. American Herbal Pharmacopoeia

and Therapeutic Compendium. Santa Cruz: AHP,

2002:37.

99. Huntley A, Ernst E. A systematic review of the safety of

black cohosh. Menopause 2003; 10(1):58–64.

100. Cohen SM, O’Connor AM, Hart J, et al. Autoimmune hepatitis

associated with the use of black cohosh: a case study.

Menopause 2004; 11(5):575–577.

101. Levitsky J, Alli TA, Wisecarver J, et al. Fulminant liver failure

associated with the use of black cohosh. Dig Dis Sci

2005; 50(3):538–539.

102. Lontos S, Jones RM, Angus PW, et al. Acute liver failure

associated with the use of herbal preparations containing

black cohosh. Med J Aust 2003; 179(7):390–391.

103. Lynch CR, Folkers ME, Hutson WR. Fulminant hepatic failure

associated with the use of black cohosh: a case report.

Liver Transpl 2006; 12(6):989–992.

104. Whiting PW, Clouston A, Kerlin P. Black cohosh and other

herbal remedies associated with acute hepatitis. Med J Aust

2002; 177(8):440–443.

105. U.S. Nebraska District Court case number 8:05-cv-00066;

Document # 90–97 and 90–98.

106. Betz JM, Anderson L,Avigan MI, et al. Black cohosh: considerations

of safety and benefit. Nutr Today 2009; 44(4):155–

162.

107. USP. Interim Revision Announcement. USP Pharmacopeial

Forum 33(5) (September–October), 2007:954–962.

108. http://abc.herbalgram.org/site/PageServer?pagename =

PR 103107. Accessed February 6, 2010.

109. USP 31—NF 26, 2008:908–912.

110. Kesselkaul O. Treatment of climacteric disorders with

Remifemin. Med Monatsschr. 1957; 11(2):87–88.

111. Schotten EW. Erfahrungen mit dem Cimicifuga-Praparat

Remifemin. Landarzt 1958; 34(11):353–354.

112. StarfingerW. Therapie mit ostrogen wirksamen Pflanzenextrakten.

Medizin Heute 1960; 9(4):173–174.

74 Fabricant et al.

113. Brucker A. Essay on the phytotherapy of hormonal disorders

in women. MedWelt 1960; 44:2331–2333.

114. Heizer H. Criticism on Cimicifuga therapy in hormonal

disorders in women. Med Klin 1960; 55:232–233.

115. Gorlich N. Treatment of ovarian disorders in general practice.

Arztl Prax 1962; 14:1742–1743.

116. Schildge E. Essay on the treatment of premenstrual and

menopausal mood swings and depressive states. Ringelh

Biol Umsch 1964; 19(2):18–22.

117. Stolze H. Der andere weg, Klimacterische Beschwerden zu

behandlen. Gyne 1982; 3:14–16.

118. Daiber W. Klimakterische Beschwerden: ohne Hormone

zum Erfolg. Arzt Prax 1983; 35:1946–1947.

119. VorbergG. Therapy of climacteric complaints. Z Allgemeinmed

1984; 60:626–629.

120. Warnecke G. Influence of a phytopharmaceutical on climacteric

complaints. MeizinischeWelt 1985; 36:871–874.

121. StollW. Phytotherapeutikum beeinflusst atrophischesVaginalepithel.

Doppelblindversuch cimicifuga vs ostrogenpraparat.

Therapeutikon 1987; 1:23–31.

122. Petho A. Klimakterische beschwerden. Umsteelung einer

Hormonbehandlung auf ein pflanzliches Gynakologikum

moglich? Arzt Prax 1987; 38:1551–1553.

123. Lehmann-Willenbrock E, Riedel H-H. Clinical and endocrinological

studies on the therapy of ovarian defunctionalization

symptoms after hysterectomy sparing the adnexa

(in German). Zentralbl Gynakol 110: 611–618 1988.

124. Baier-Jagodinski G. Praxisstudie mit Cimisan bei klimakterischen

Beschwerden, Pramenstruallen syndrom und Dysmenorrhoe.

Natur Heilpraxis Naturmedizin 1995; 48:1284–

1288.

125. Nesselhut T, Liske E. Pharmacological measures in postmenopausal

women with an isopropanolic aqueous extract

of Comicifugae racemosae rhizoma. Menopause 1999; 6(4):331.

126. Verhoeven MO, van der Mooren MJ, van de Weijer

PH, et al; CuraTrial Research Group. Effect of a combination

of isoflavones and Actaea racemosa Linnaeus

on climacteric symptoms in healthy symptomatic perimenopausal

women: a 12-week randomized, placebocontrolled,

double-blind study. Menopause 2005; 12(4):412–

420.

127. Nappi RE, Malavasi B, Brundu B, et al. Efficacy of Cimicifuga

racemosa on climacteric complaints: a randomized study

versus low-dose transdermal estradiol. Gynecol Endocrinol

2005; 20(1):30–35.

128. Frei-Kleiner S, Schaffner W, Rahlfs VW, et al. Cimicifuga

racemosa dried ethanolic extract in menopausal disorders:

a double-blind placebo-controlled clinical trial. Maturitas

2005; 51(4):397–404.

129. Raus K, Brucker C, Gorkow C, et al. First-time proof of endometrial

safety of the special black cohosh extract (Actaea

or Cimicifuga racemosa extract) CR BNO 1055. Menopause

2006; 13(4):678–691.

130. Sammartino A, Tommaselli GA, GarganoV, et al. Short-term

effects of a combination of isoflavones, lignans and Cimicifuga

racemosa on climacteric-related symptoms in postmenopausal

women: a double-blind, randomized, placebocontrolled

trial. Gynecol Endocrinol 2006; 22(11):646–

650.

131. Gurley BJ, Barone GW, Williams DK, et al. Effect of milk

thistle (Silybum marianum) and black cohosh (Cimicifuga

racemosa) supplementation on digoxin pharmacokinetics in

humans. Drug Metab Dispos 2006; 34(1):69–74.

132. Rebbeck TR, Troxel AB, Norman S, et al. A retrospective

case-control study of the use of hormone-related supplements

and association with breast cancer. Int J Cancer 2007;

120(7):1523–1528.

133. Hirschberg AL, Edlund M, Svane G, et al. An isopropanolic

extract of black cohosh does not increase mammographic

breast density or breast cell proliferation in postmenopausal

women. Menopause 2007; 14(1):89–96.

134. Gurley BJ, Swain A, Hubbard MA, et al. Clinical assessment

of CYP2D6-mediated herb-drug interactions in humans: effects

of milk thistle, black cohosh, goldenseal, kava kava,

St. John’s wort, and Echinacea. Mol Nutr Food Res. 2008;

52(7):755–763.

Cascara Sagrada

Glossary, HerbsSuccess Chemistry Staff

Cascara Sagrada Rhamnus purshiana De Candolle is the largest species of

buckthorn.

Occasionally growing up to 15 m in height;

however, it is more commonly a large shrub or small

tree (5–10 m) (1–5). Rhamnus purshiana is native to the Pacific

Northwest United States and south western Canada

(1–5). Rhamnus is the generic name for buckthorn, and

the species name, purshiana, was given in honor of the

German botanist Friedrich Pursh (4). The crude drug consists

of the dried bark of the tree, which is officially known

as Cascara or cascara sagrada, Spanish for “sacred bark”

(1–4). The dried aged bark of the tree has been used by Native

Americans for centuries as a laxative. It was accepted

into medical practice in the United States in 1877 as a commonly

used laxative and was the principal ingredient in

many over-the-counter (OTC) laxative products. Cascara

was first listed in the U.S. Pharmacopeia (USP) in 1890 as

a laxative mild enough for use in treating the elderly and

children. Products that were official in the USP included

cascara sagrada extract, fluid extract, aromatic fluid extract,

and tablets. In 2002, the U.S. Food and Drug Administration

issued a final rule concerning the status of cascara

sagrada (including casanthranol, cascara fluid extract aromatic,

cascara sagrada bark, cascara sagrada extract, and

cascara sagrada fluid extract) in OTC drug products (5).

The final rule stated that cascara sagrada in OTC drug

products is not generally recognized as safe and effective

or is misbranded (6).

 

BACKGROUND

General Description

The shrub or small tree of R. purshiana De Candolle has

elliptical leaves, greenish flowers, and black berries. It

ranges in height from 4.5 to 15mand has a reddish-brown

bark (4). Most of the commercial production comes from

Oregon,Washington, and southern British Columbia. The

bark is collected in spring (April/May) and early summer

by stripping from wild trees scattered throughout the

native forests. It is removed by making longitudinal incisions

and peeling off sections, which tend to roll into large

quills. Trees are also felled and the bark is removed from

the larger branches. The bark is then air dried, with the

inner surface protected from the sun in order to preserve

its yellow color. The dried bark is allowed to mature for

1 or 2 years before use in commercial preparations (4). The

fresh bark contains chemical constituents that act as a gastrointestinal

(GI) irritant and emetic; thus, the bark must

be aged for at least 1 year prior to human use. Cascara

bark and its preparations have been used for centuries by

the Pacific Northwest Native Americans, as well as the

European settlers, and cascara preparations are now used

worldwide as a laxative (5).

Commercial preparations of cascara (Cortex Rhamni

Purshianae) consist of the dried, whole, or fragmented

bark of R. purshiana. The bark and its preparations are

official in the pharmacopoeias of many countries (1,7–9).

Cascara was first listed in the USP in 1890 as a laxative.

The official listing of cascara in USP 25 (9) defined it as

the dried bark (at least 1-year old) of R. purshiana, yielding

not less than 7% of total hydroxyanthracene derivatives

calculated as cascaroside A on a dried basis. Not less than

60% of the total hydroxyanthracene derivatives consist of

cascarosides, calculated as cascaroside A (9).

 

CHEMISTRY AND PREPARATION OF PRODUCTS

The chemistry of cascara has been extensively investigated

and numerous quinoid constituents are reported

to be present in the bark (1). Much of the chemical and

pharmacological research on cascara was performed over

50 years ago, and anthraquinone glycosides were established

as the active constituents of the bark (5). Hydroxyanthracene

glycosides make up 6% to 9% of the bark,

of which 70% to 90% is C-10 glycosides, with aloins A

and B and desoxy aloins A and B (= chrysalis) accounting

for 10% to 30% (1). The cascarosides A and B and

cascarosides C and D are diastereoisomeric pairs derived

from 8--O-glucosides of aloin A and B and 8-O-glucosyl-

11-deoxy loin, respectively, and constitute 60% to 70%

of the total glycosides (1). Hydrolysis of the cascarosides

cleaves the O-glycosidic bonds to yield aloins (barbaloin

and chrysaloin). The cascarosides are not bitter, whereas

most of their hydrolysis products (the aloins) are very

bitter. Both the USP and the European Pharmacopoeia

recognize the cascarosides and aloins as the active constituents

of cascara and have chemical assay procedures

for determining these glycosides (7–9).

Other major hydroxyanthracene glycosides include

the hydroxy anthraquinones chrysophanol-8-O-glucoside

and aloe-emodin-8-O-glucoside at a concentration of 10%

to 20% (10). In the fresh bark, anthraquinones are present

in the reduced form and are converted by oxidation to their

corresponding parent anthraquinone glycosides during

drying and storage (3).

Dosage Forms and Dose

Cascara sagrada is available as extracts, fluidextracts, and

tablets (9).

Cascara Sagrada

one-half dose in the morning and at bedtime) of standardized

preparations is 20 to 30 mg of hydroxyanthracene

derivatives calculated as cascaroside A (dried aged bark,

0.25–1 g) (1). Do not exceed the recommended dose and do

not use this dose for more than 1 to 2 weeks continuously.

 

PRECLINICAL STUDIES

Toxicity

While there are no specific data describing the carcinogenicity

or mutagenicity for cascara sagrada, there are

data available for emodin, one of the naturally occurring

anthraquinones present in cascara (11–18). There are

several studies reporting genotoxic and mutagenic effects

both in vitro and in vivo for emodin and its derivatives,

causing them to be classified as potential carcinogens (12–

18). In vitro, the toxicity of 1,8-dihydroxyanthraquinone,

such as emodin, may involve redox cycling between the

quinone and the semiquinone radical generating reactive

oxygen species (ROS), resulting in lipid peroxidation, protein

damage, and DNA oxidation (16,19,20). For example,

treatment of Reuber hepatoma and fibroblast Balb/3T3

cells with various anthraquinones resulted in the formation

of 8-oxo-dG (16). In addition, concentrations of 50 M

aloe–emodin increased DNA damage as measured by

the single-cell gel electrophoresis assay (COMET assay)

(21). Aloe–emodin and other anthraquinones also dose

dependently induced tk-mutations and micronuclei in

mouse lymphoma L5178Y cells and inhibited topoisomerase

II–mediated decatenation in a DNA decatenation

assay 21,22). The authors suggested that anthraquinones

bind noncovalently to DNA and inhibit the catalytic function

of topoisomerase II, which can lead to DNA breakage

by competing with the DNA binding site of the enzyme

23). It is also possible that anthraquinones can covalently

bind to DNA as observed with other quinones, such as p benzoquinone

(24,25). Binding of anthraquinones toDNA

might also facilitate DNA oxidation due to their high potency

of generating ROS. Besides the above-mentioned

effects of redox cycling by anthraquinones, it is also reported

that production of ROS by emodin can cause an

immunosuppressive effect in human mononuclear cells

and might result in apoptosis in A549 cells in vitro 19).

In vivo toxicology was assessed by the National Toxicology

Program and published in 2001 (11). Reports that

1,8-dihydroxyanthraquinone caused tumors in the GI tract

of rats led to the investigation of emodin in rodents, as

this compound is structurally similar and was reported

to be mutagenic in bacteria. The acute and chronic toxicities

of emodin were investigated in rodents exposed to

emodin in feed for 16 days, 14 weeks, or 2 years. In the

16-day study, rodents were fed diets containing average

daily doses equivalent to 50, 170, 480, 1400, or 3700 mg/kg

body weight for males and 50, 160, 460, 1250, or 2000

mg/kg body weight for females. The results showed that

the mean body weights of males and females exposed

to 480 mg/kg or greater were significantly lower than

those of the controls. Macroscopic lesions were observed

in the gallbladder and kidney of rats exposed to the highest

doses of 1400 or 3700 mg/kg. In the 14-week study,

rats were fed diets containing approximately 20, 40, 80,

170, or 300 mg/kg for males and females. Mean body

weights of males exposed to 170 mg/kg or greater and

females exposed to 80 mg/kg or greater were significantly

lower than those of the controls. In rats exposed to 170 or

300 mg/kg of emodin, increases in platelet counts and

decreases in total serum protein and albumin concentrations

were observed. Relative kidney weights of rats exposed

to 80 mg/kg or greater and relative lung and liver

weights of rats exposed to 40mg/kgor greater were significantly

increased compared to the control groups. The incidences

and severities of nephropathy were increased in

males and females exposed to 40 mg/kg or greater. In the

chronic toxicity study (2 years), groups of 65 male and 65

female rats were fed diets containing emodin at an equivalent

to average daily doses of approximately 110, 320, or

1000 mg/kg to males and 120, 370, or 1100 mg/kg to

females for 105 weeks. Survival of exposed males and females

was similar to that of the controls. There were negative

trends in the incidences of mononuclear cell leukemia

in both male and female rats and incidence of leukemia in

the group fed 1000 mg/kg was significantly decreased.

At the 12-month interim evaluation, nephropathy was

slightly higher (11).

In terms of genetic toxicology, emodin was mutagenic

in Salmonella typhimurium strain TA100 in the

presence of S9 activation; however, no mutagenicity was

detected in strain TA98, with or without S9 (11). Chromosomal

aberrations were induced in cultured Chinese

hamster ovary cells treated with emodin, with or without

metabolic activation by S9. In the rat bone marrow

micronucleus test, administration of emodin by three intraperitoneal

injections gave negative results. Results of

acute-exposure (intraperitoneal injection) micronucleus

tests in bone marrow and peripheral blood erythrocytes of

male and female mice were also negative. In a peripheral

blood micronucleus test on mice from the 14-week study,

negative results were seen in male mice, but a weak positive

response was observed in similarly exposed females.

The results of these investigations show no evidence

of carcinogenic activity of emodin in male F344/N rats

in the two-year study. There was equivocal evidence of

carcinogenic activity of emodin in female F344/N rats and

male B6C3F1 mice. There was no such evidence in female

B6C3F1 mice exposed to 312, 625, or 1250 ppm (11).

Other investigations of the carcinogenic potential of

cascara have been carried out in rodents. In one study,

the effects of the laxative bisacodyl (4.3 and 43 mg/kg)

and cascara (140 and 420 mg/kg) on the induction of

azoxymethane (AOM)-induced aberrant crypt foci (ACF)

and tumors in rats were investigated (26). Animals were

treated with AOM and laxatives (alone or in combination)

for 13 weeks. The results demonstrated that bisacodyl (4.3

and 43 mg/kg), given alone, did not induce the development

of colonic ACF and tumors. However, bisacodyl

(4.3 mg/kg) coupled with AOM increased the number of

crypts per focus but not the number of tumors. Bisacodyl

(43 mg/kg) significantly increased the number of crypts

per focus and tumors. Cascara (140 and 420 mg/kg)

did not induce the development of colonic ACF and tumors

and did not modify the number of AOM-induced

ACF and tumors (27). Results from another study were

similar. Dietary exposure to high doses of these glycosides

for 56 successive days did not induce the appearance

of ACF or increase in incidence of ACF induced by

126 Soni and Mahady

1,2-dimethylhydrazine (DMH). However, in rats treated

with both DMH and the highest dose of glycosides, the

average number of aberrant crypts per focus, considered

a consistent predictor of tumor outcome, was higher than

that in rats given DMH alone (26).

 

CLINICAL STUDIES

Laxative Effects

Cascara sagrada is an anthraquinone laxative and is

used for short-term treatment of occasional constipation

(1,28,29). The laxative effects of cascara are primarily due

to the anthraquinone glycosides, the cascarosides A–D

(1,5). Other anthranoid derivatives that may be active include

emodin anthrone-6-O-rhamnoside (franguloside),

and physcion and chrysophanol in glycosidic and aglycone

forms (30,31). Anthraquinone laxatives are prodrugs

in that after oral administration, the hydroxyanthracene

glycosides are poorly absorbed in the small intestine, but

are hydrolyzed in the colon by intestinal bacteria to form

pharmacologically active metabolites, which are partly absorbed

there (28,30); this acts as a stimulant and irritant to

the GI tract (29).

The mechanism of action of cascara is similar to that

of senna in that the action is twofold: (i) stimulation of

colonic motility, resulting in augmented propulsion, and

accelerated colonic transit (which reduces fluid absorption

fromthe fecal mass); and (ii) an increase in the paracellular

permeability across the colonic mucosa, probably due to

an inhibition of Na+, K+-adenosine triphosphatase or an

inhibition of chloride channels (30,32), which results in an

increase in the water content in the large intestine (29,32).

The laxative effect of cascara is generally not observed

before 6 to 8 hours after oral administration. The hydroxyanthracene

glycosides are excreted predominantly in the

feces but are excreted to some extent in urine as well,

producing an orange color; anthrones and anthranols also

pass into breast milk (30).

Anthraquinone laxatives may produce an excessive

laxative effect and abdominal pain. The major symptoms

of overdose are gripes and severe diarrhea, with consequent

losses of fluid and electrolytes (29). Treatment

should be supported with generous amounts of fluid.

Electrolytes should be monitored, particularly potassium.

This is especially important in children and the elderly.

Renal excretion of the compounds may cause abnormal

coloration of urine (yellow–brown to reddish depending

on the pH of the urine). Large doses may cause nephritis.

Melanotic pigmentation of the colonic mucosa (pseudomelanosis

coli) has been observed in individuals who

abuse anthraquinone laxatives. Pigmentation is usually

benign and reverses within 4 to 12 months of discontinuation

of the products (29).

Contraindications and Precautions

Patients should be warned that certain constituents of cascara

sagrada are excreted by the kidney and may color

the urine (harmless). Rectal bleeding or failure to have a

bowel movement after the use of a laxative may indicate

a serious condition. Laxatives containing anthraquinone

glycosides should not be used for periods longer than 1 to

2 weeks (29). Decreased intestinal transit time may result

in reduced absorption of orally administered drugs (1).

Electrolyte imbalances such as increased loss of potassium

may potentiate the effects of cardiotonic glycosides (e.g.,

digitalis). Existing hypokalemia resulting from long-term

laxative abuse can also potentiate the effects of antiarrhythmic

drugs that affect potassium channels to change

sinus rhythm, such as quinidine. The induction of hypokalemia

by drugs such as thiazide diuretics, adrenocorticosteroids,

or liquorice root may be enhanced, and

electrolyte imbalance may be aggravated (28).

Chronic use (>2 weeks) may cause dependence and

need for increased doses, and an atonic colon with impaired

function (29). It may also lead to pseudomelanosis

coli (harmless) and to an aggravation of constipation with

dependence and possible need for increased dosages.

Chronic abuse with diarrhea and consequent fluid and

electrolyte losses (mainly hypokalemia) may cause albuminuria

and hematuria, and may result in cardiac and

neuromuscular dysfunction (1).

Anthraquinone stimulant laxatives, such as cascara,

should not be administered to patients with intestinal obstruction

and stenosis, atony, severe dehydration states

with water and electrolyte depletion, or chronic constipation

(1,29). Cascara should not be administered to patients

with inflammatory intestinal diseases, such as appendicitis,

Crohn disease, ulcerative colitis, and irritable bowel

syndrome, or in children younger than 12 years (1,29). As

with other stimulant laxatives, cascara is contraindicated

in patients with cramps, colic, hemorrhoids, nephritis, or

any undiagnosed abdominal symptoms such as pain, nausea,

or vomiting (29).

Because of the pronounced action on the large intestine

and insufficient toxicological investigations, products

containing cascara should not be administered to pregnant

women (33,34). Furthermore, anthranoid metabolites are

excreted into breast milk. Thus, cascara should not be used

during lactation, due to insufficient data available to assess

the potential for pharmacological effects in the breast-fed

infant (33).

 

Adverse Reactions

In single doses, cramp-like discomfort of the GI tract may

occur, which may require a reduction of dosage. Overdose

can lead to colicky abdominal spasms and pain,

as well as the formation of thin, watery stools. Longterm

laxative abuse may lead to electrolyte disturbances

(hypokalemia, hypocalcemia), metabolic acidosis, malabsorption,

weight loss, albuminuria, and hematuria (35,36).

Weakness and orthostatic hypotension may be exacerbated

in elderly patientswhenstimulant laxatives are used

repeatedly. Secondary aldosteronism may occur due to renal

tubular damage after aggravated use. Steatorrhea and

protein-losing gastroenteropathy with hypoalbuminemia

have also been reported in laxative abuse (36). Melanotic

pigmentation of the colonic mucosa (pseudomelanosis

coli) has been observed in individuals taking anthraquinone

laxatives for extended time periods (29,36–

39). The pigmentation is clinically harmless and usually

reversible within 4 to 12 months after the drug is discontinued

(36–40). Conflicting data exist on other toxic effects

such as intestinal–neuronal damage after long-term use

(36). Use of the fresh drug may cause severe vomiting,

Cascara Sagrada 127

with possible spasms (30). Cases of allergic respiratory

diseases after occupational exposure to cascara have been

reported (41). Cascara sagrada is an etiologic agent of IgEmediated

occupational asthma and rhinitis. One case of

cholestatic hepatitis, complicated by portal hypertension,

has been attributed to the ingestion of cascara in one patient

who was also known to abuse alcohol and take a

number of other prescription medications (42).

 

CURRENT REGULATORY STATUS

Prior to June 1998, cascara sagrada was recognized by the

Food and Drug Administration (FDA) as a category I (safe

and effective) OTC preparation (monograph). In 2002, the

U.S. FDA issued a final rule concerning stimulant laxatives

including cascara sagrada (including casanthranol,

cascara fluid extract aromatic, cascara sagrada bark, cascara

sagrada extract, and cascara sagrada fluid extract) in

OTC drug products, stating that they are not generally recognized

as safe and effective or are misbranded (6). This

final rule was based on a decision made by the agency

after it had requested mutagenicity, genotoxicity, and carcinogenicity

data on cascara in 1998. No comments or data

were provided to the FDA for cascara; thus on the basis

the lack of data and information and the failure of any

persons to submit new data from carcinogenicity studies,

the agency has determined that these laxative should be

deemed not generally recognized as safe and effective for

OTC use and has thus reclassified these ingredients to category

II (non monograph) (6). According to the FDA, products

containing aloe and cascara sagrada ingredients must

be reformulated or discontinued; the stimulant laxatives

must therefore be deleted or replaced. Reformulated products

will also need to be relabeled. This final rule is part

of FDA’s ongoing OTC drug product review. However,

these products may still be sold as dietary supplements

under the Dietary Supplements Health and Education Act

of 1994.

 

REFERENCES

1. Farnsworth NR, Fong HHS, Mahady GB. Cortex Rhamni

Purshianae, WHO Monographs on Selected Medicinal

Plants. Geneva, Switzerland: WHO Publications 2001:2.

2. Gathercoal EN,Wirth EH. Pharmacognosy. Philadelphia: Lea

and Febiger, 1947:411–416.

3. Tyler VE, Bradley LR, Robbers JE. Pharmacognosy, 9th.

Philadelphia: Lea and Febiger, 1988:62–63.

4. Youngken HW. Rhamnaceae (buckthorne family). Textbook

of Pharmacognosy. Philadelphia: The Blakiston Company,

1950:543–549.

5. Leung AY. Cascara sagrada—New standards are needed.

Drug Cosmet Ind 1977; 12:42.

6. Food and Drug Administration, Department of Health

and Human Services. Status of certain additional over-thecounter

drug category II and III active ingredients. Final rule.

Fed Regist 2002; 67:31125–31127.

7. European Pharmacopoeia, 2nd edn. Strasbourg, France:

Council of Europe, 2002:549.

8. Pharmacop e Fran aise. Paris, France: Adrapharm, 1996: 1–5.

9. The United States Pharmacopeia 25. Rockville, MD: The

United States Pharmacopeia Convention Inc, 2002:281–282.

10. Bruneton J. Pharmacognosy, Phytochemistry, Medicinal

Plants. Paris, France: Lavoisier, 1995:360–361.

11. National Toxicology Program. NTP Toxicology and Carcinogenesis

Studies of EMODIN (CAS NO. 518–82-1) Feed Studies

in F344/N Rats and B6C3F1 Mice. Natl Toxicol Program

Tech Rep Ser 2001; 493:1–278.

12. Masuda T, Ueno Y. Microsomal transformation of emodin

into a direct mutagen. Mutat Res 1984; 125:135–144.

13. Masuda T, Haraikawa K, Morooka N, et al. 2-

Hydroxyemodin, an active metabolite of emodin in the hepatic

microsomes of rats. Mutat Res 1985; 149:327–332.

14. Morita H, Umeda M, Masuda T, et al. Cytotoxic and mutagenic

effects of emodin on cultured mouse carcinoma FM3

A cells. Mutat Res 1988; 204:329–332.

15. Murakami H, Kobayashi J, Masuda T, et al. 2-

Hydroxyemodin, a major hepatic metabolite of emodin in

various animals and its mutagenic activity. Mutat Res 1987;

180:147–153.

16. Akuzawa S, Yamaguchi H, Masuda T, et al. Radicalmediated

modification of deoxyguanine and deoxyribose

by luteoskyrin and related anthraquinones. Mutat Res 1992;

266:63–69.

17. Krivobok S, Seigle-Murandi F, Steiman R, et al. Mutagenicity

of substituted anthraquinones in the Ames/Salmonella

microsome system. Mutat Res 1992; 279:1–8.

18. Zhang YP, Sussman N, Macina OT, et al. Prediction of the

carcinogenicity of a second group of organic chemicals undergoing

carcinogenicity testing. Environ Health Perspect

1996; 104(suppl. 5):1045–1050.

19. Huang HC, Chang JH, Tung SF, et al. Immunosuppressive

effect of emodin, a free radical generator. Eur J Pharmacol

1992; 211:359–364.

20. Rahimipour S, Bilkis I, Peron V, et al. Generation of free

radicals by emodic acid and its [D-Lys6]GnRH-conjugate.

Photochem Photobiol 2001; 74:226–236.

21. Mueller SO, Eckert I, Lutz WK, et al. Genotoxicity of the laxative

drug components emodin, aloe-emodin and danthron

in mammalian cells: Topoisomerase II mediated? Mutat Res

1996; 371:165–173.

22. Mueller SO, Lutz WK, Stopper H. Factors affecting the genotoxic

potency ranking of natural anthraquinones in mammalian

cell culture systems. Mutat Res 1998; 414:125–129.

23. Mueller SO, Stopper H. Characterization of the genotoxicity

of anthraquinones in mammalian cells. Biochim Biophys

Acta 1999; 1428:406–414.

24. Bolton JL, Trush MA, Penning TM, et al. Role of quinones in

toxicology. Chem Res Toxicol 2000; 13:135–160.

25. Levay G, Pongracz K, Bodell WJ. Detection of DNA

adducts in HL-60 cells treated with hydroquinone and

p-benzoquinone by 32P-postlabeling. Carcinogenesis 1991;

12:1181–1186.

26. Mereto E, Ghia M, Brambilla G. Evaluation of the potential

carcinogenic activity of senna and cascara glycosides for the

rat colon. Cancer Lett 1996; 101:79–83.

27. Borrelli F, Mereto E, Capasso F, et al. Effect of bisacodyl and

cascara on growth of aberrant crypt foci and malignant tumors

in the rat colon. Life Sci 2001; 69:1871–1877.

28. Cascara Sagrada Bark. The Complete German Commission E

Monographs. Austin, TX: American Botanical Council, 1998.

29. Goodman and Gilman’s: The Pharmacological Basis of Therapeutics;

9th edn. New York: McGraw-Hill, 2001.

30. Bradley PR. Cascara sagrada. British Herbal Compendium,

Dorset: British Herbal Medicine Association 1992; 1:52–54.

31. Westendorf J. Anthranoid derivatives—Rhamnus species.

Adverse Effects of Herbal Drugs, vol. 2. Heidelberg:

Springer-Verlag, 1993:70.

32. deWitte P. Metabolism and pharmacokinetics of the anthranoids.

Pharmacology 1993; 47(suppl. 1):86–97.

33. Lewis JH, Weingold AB. The use of gastrointestinal drugs

during pregnancy and lactation. Am J Gastroenterol 1985;

80:912–923.

128 Soni and Mahady

34. Physician’ Desk Reference. Montvale, NJ: Medical Economics

Company, 1998.

35. Godding EW. Therapeutics of laxative agents with special

reference to the anthraquinones. Pharmacology 1976;

14(suppl. 1):78–108.

36. Muller-Lissner SA. Adverse effects of laxatives: Facts

and fiction. Pharmacology 1993; 47(suppl. 1):138–

145.

37. Heizer WD. Protein-losing gastroenteropathy and malabsorption

associated with factitious diarrhoea. Ann Intern

Med 1968; 68:839–852.

38. Loew D. Pseudomelanosis coli durch Anthranoide. Z Phytother

1994; 16:312–318.

39. Patel PM, Selby PJ, Deacon J, et al. Anthraquinone laxatives

and human cancer. Postgrad Med J 1989; 65:216–217.

40. Kune GA. Laxative use not a risk for colorectal cancer: Data

fromthe Melbourne colorectal cancer study.ZGasteroenterol

1993; 31:140–143.

41. Giavina-Bianchi PF Jr, Castro FF, Machado ML, et al. Occupational

respiratory allergic disease induced by Passiflora alata

and Rhamnus purshiana. Ann Allergy Asthma Immunol 1997;

79:449–454.

42. Nadir A, Reddy D, Van Thiel DH. Cascara sagrada-induced

intrahepatic cholestasis causing portal hypertension: Case

report and review of herbal hepatotoxicity. Am J Gastroenterol

2000; 95:3634–3637.

Dong Quai

HerbsSuccess Chemistry Staff

The root of dang gui (Angelica sinensis; also known as

dong quai; Fig. 1) is one of the primary botanicals used

in traditional Chinese medicine (TCM) for the treatment

of gynecological and circulatory conditions.

primary use is to both build and promote the movement

of blood, and on the basis of these actions it is utilized for

a myriad of conditions. Despite its widespread use among

practitioners of TCM, there have been few clinical studies

regarding its efficacy, although preclinical data support

many of these traditional uses as well as suggest benefit

for numerous other uses.

Traditional and Modern Uses Dang gui grows at high altitudes in comparatively cold,

damp, mountainous regions in China and other parts of

East Asia.

The plant is a fragrant perennial that has smooth

purplish stems and bears umbrella-shaped clusters (umbels)

of white flowers that grow to approximately 3 ft

in height. Dang gui produces winged fruits in July and

September. In the earliest known herbal text of China, the

Divine Husbandman’s Classic of the Materia Medica (Shen

Nong Ben Cao Jing), dang gui is described as a herb to

“supplement nature” (1). In the monumental 52-volume

Compendium of Materia Medica (Ben Cao Gang Mu), written

by Li Shizhen in the 16th century, dozens of uses for

dang gui were elaborated. These included the following:

to tonify the five major viscera, especially the heart; to generate

flesh; to stop headache, back pain, menstrual pain,

toothache, and pain associated with the “belt channel”

(dai mai); to treat a wide range of skin sores and rashes;

and to correct menstrual problems such as irregular menstruation,

amenorrhea, and dysmenorrhea (2).

Modern research has focused on the use of dang

gui for its ability to enhance circulation and oxygenation

in hypoxic conditions specifically in regard to brain and

cardiovascular effects. Despite the widespread popularity

and use of dang gui in gynecology, there is a lack of

research in modern English language journals regarding

this use, though some data suggest estrogenic and both

uterine relaxant and uterine stimulatory activity, depending

on the fraction studied. A number of studies report

on the ability of dang gui to promote the healing of tissues,

specifically in ulcerative colitis and gastric ulcers,

and other studies have focused on its anticancer and hepatoprotective

effects, among others.

Chemistry and Preparation of Products

The primary analytes of interest in dang gui are the Zalkylphthalides,

most notably ligustilide (Fig. 2), low- and

high-molecular-weight polysaccharides, and ferulic acid

(Fig. 2). The alkylphthalides are present in the essential

oil and are strongly aromatic. Both the crude extract and

individual compounds have been correlated with biological

activity (see preclinical studies; clinical studies). The

crude extract has been associated with positive human

clinical effects for the treatment of chronic obstructive pulmonary

disease (COPD) and COPD with hypertension,

increasing blood volume in postischemic patients, and

decreasing platelet aggregation (3). The alkylphthalides

and ferulic acid inhibit platelet aggregation and the formation

of platelet thromboxane A2 (4–6) and elicit in vitro

spasmolytic activity, increase coronary blood flow, slightly

decrease myocardial contractility, and markedly prolong

the effective refractory period (7). Total extracts have also

been associated with hepatoprotective effects. Thus dang

gui is utilized in portal hypertension and veno-occlusive

disease. At least part of this activity is associated with

the demonstrated antioxidant activity of ligustilide, ferulic

acid, and polysaccharides (8–10), as well as the ability

of dang gui to promote hepatic microcirculation. In human

clinical trials both an aqueous extract and ligustilide have

been found to be effective in treating dysmenorrhea (11).

Dang gui polysaccharides stimulate hematopoiesis and,

along with ferulic acid, elicit immunomodulatory activity

(e.g., increased phagocytosis) (12,13). Ligustilide and ferulic

acid elicit a strong uterine spasmolytic effect (14–17).

All of these actions are consistent with the use of dang gui

in traditional Chinese medicine.

Investigations of polysaccharides derived from

dang gui, specifically in conjunction with their potential

immunomodulatory effects have been conducted. The

polysaccharides, named A. sinensis polysaccharide fractions

(APF 1,APF2,APF3) and crude angelica polysaccharide

consist of rhamnose, galacturonic acid, glucose, galactose,

mannose, and arabinose in various ratios (18,19).

In TCM, the roots of dang gui are commonly prepared

as a tea, extract, syrup, tablet, or capsule. In supplement

form, dang gui occurs predominantly in tablets

and capsules, and occasionally in tinctures. As with the

majority of Chinese herbs, dang gui is most often used in

combination with other botanicals and is predominantly

featured in formulas for promoting healthy gynecological

and cardiovascular systems and for a healthy liver.

Different portions of the roots are used for different indications.

The whole roots are said to “harmonize” the

Whole dang gui (Angelica sinensis) roots.

blood; the dang gui root bodies (dang gui tou; ) are

used to build and nourish the blood and are commonly

included in soups for convalescence and blood deficiency;

the tails (dang gui wei; ) are predominantly used to

“break the blood” and prevent and treat abnormal blood

stagnation.

Pharmacokinetics

There are limited data on the pharmacokinetics of some

of the compounds contained within dang gui. In a study

of the bioavailability of ferulic acid in humans (n = 5), the

peak time for maximal urinary excretion of ferulic acid

following the consumption of 360 to 728 g tomatoes (providing

approximately 21 to 44 mg ferulic acid) was 7 to

9 hours (20). A considerable proportion of ferulic acid was

excreted as glucuronide in all subjects. The recovery of

ferulic acid in the urine, on the basis of total free ferulic

acid and feruloyl glucuronide excreted, was 11% to 25% of

that ingested. The bioavailability of ferulic acid from beer

is consistent with the uptake of ferulic acid from other

dietary sources, such as tomatoes (21). Urinary and biliary

metabolites of ferulic acid were primarily glucuronic

acid and glycine conjugates of ferulic acid and vanillic

acid. Major constituents of dang gui.

model and suggest that ferulic acid is rapidly and almost

completely absorbed from the intestinal tract (23). It has

also been reported that ferulic acid crosses the blood–brain

barrier, although in very low concentrations (24). The major

metabolites of ferulic acid are nontoxic and water soluble,

being excreted through the urine and bile as free acids

and acid conjugates.

PRECLINICAL STUDIES

Pharmacodynamics

Dang gui is one of the most widely used of all Chinese

botanicals. Historically and in modern Chinese medicine,

it has been primarily used as a general blood tonic for the

TCM diagnosis of blood deficiency, a syndrome closely

related, but not exactly analogous or limited, to anemia.

Dang gui has also been used for a myriad of gynecological

indications, although there has been very little research

done in this regard in English language journals. More

recently, pharmacological research has focused on the potential

of constituents of dang gui to elicit cardiovascular,

hematopoietic, hepatoprotective, antioxidant, antispasmodic,

and immunomodulatory effects. Chinese botanicals

are most often used in multi-ingredient formulas

rather than as single agents. Therefore, there are very few

clinical trials on dang gui alone, although numerous preclinical

studies exist. Due to the lack of primary English

language literature, it is difficult to adequately access or

adequately review the available data by non-Chinese language

readers. Another difficulty in reviewing the available

studies is that many of the investigations are of disease

patterns that are unique to TCM and do not have

well-defined corresponding Western diagnoses, or viceversa;

studies are conducted for indications not synonymous

with TCM indications. While the TCM findings are

relevant to TCM practitioners, their importance may be ignored

or even criticized by non-TCM practitioners. Study

of non-TCM indications often is conducted for purposes

of modern drug discovery and therefore can be criticized

on different grounds. Lastly, it has been reported that up

to 99% of studies presented in the Chinese medical literature

show results favoring test intervention, suggesting

the potential for a positive publication bias and hence the

need for caution in interpreting the available data (25).

Conversely, publication bias against dietary supplement

research in the primary medical literature of the United

States has been reported and may similarly limit a critical

review of investigations of herbal products (26).

The bioactive compounds most studied in dang gui

are phthalides, polysaccharides, and ferulic acid. Studies

using these compounds have reported a number of therapeutic

effects, some of which are consistent with the use

of dang gui in TCM and some of which are not. The contribution

of ferulic acid to the therapeutic effect of dang

gui is unlikely given its low concentration in crude dang

gui (0.05–0.09%). The compounds used in pharmacological

studies are often administered at doses exceeding those

available from typical dosages of dang gui root preparations.

While these data are presented, it is not possible to

extrapolate results from such studies to clinical efficacy

of orally administered crude drug products; hence, the

reported findings must be evaluated critically.

Cardiovascular and Hemorheological Effects

Clinically, dang gui is widely used for the treatment of cardiovascular

disease, specifically conditions that can benefit

from enhanced circulation and a decrease in platelet

aggregation. Preclinical studies using dang gui and some

of its constituents suggest actions and mechanisms by

which it may exert a cardiovascular effect. These include

stimulation of circulation, platelet aggregation inhibition,

decrease in myocardial oxygen consumption, and vasorelaxation

(measured as a decrease in vascular resistance;

see also effects on smooth muscle).

A number of animal studies and in vitro assays support

some of the putative cardiovascular effects of dang

gui. These include an increase in myocardial perfusion,

decrease in myocardial oxygen consumption, increase in

blood flow, decrease in vascular resistance, and inhibition

of platelet aggregation, ventricular fibrillation, and

arrhythmias (3). However, a direct extrapolation of these

findings to humans cannot be made without confirmatory

human studies. A review of the activity of sodium ferulate

reported that it both inhibits platelet aggregation and

elicits a thrombolytic activity in vitro and in vivo. These effects

were due to inhibition of cyclooxygenase and thromboxane

A2 synthase with improvements in blood viscosity,

reduction in the concentration of plasma fibrinogen,

and increase in coronary perfusion. Additional cardiovascular

effects reported include reduction of cholesterol

biosynthesis and lowering of triglycerides, improvements

in myocardial oxygen consumption, and antiarrhythmic,

antioxidant, and antiatherogenic activity (24).

Hepatoprotective Effects

A number of preclinical studies indicate that dang gui,

dang gui polysaccharides, ferulic acid, and sodium ferulate

have antioxidant effects that can protect the liver

against damage due to chemically induced toxicity. Part

of this action is due to the ability of dang gui polysaccharides

to reduce the levels of nitric oxide (24.6%), serum

alanine aminotransferase (40.8%), and serum glutathione

S-transferase (18.4%) in animals with acetaminophen induced

or carbon tetrachloride-induced liver damage

(8,9,27,28).

Gynecological Effects

Dang gui is one of the most important herbal medicines in

TCM for the treatment of menstrual disorders, especially

when used in combination with other botanicals. It has

traditionally been used to treat conditions associated with

the TCM diagnosis of “blood stasis” and “blood vacuity,”

which can be correlated with Western syndromes such

as amenorrhea, dysmenorrhea, endometriosis, uterine fibroids,

and certain forms of infertility. Its efficacy appears

to have been demonstrated over the 750-year history of its

use for these indications and its continued, and apparent,

successful use by modern practitioners of TCM. However,

there are few studies substantiating these effects (11,29),

and those that are available lack methodological rigor.

Using ELISA-type immunoassays of two steroidregulated

proteins, presenelin-2 and prostate-specific antigen,

in breast carcinoma cell line BT-474, researchers reported

that dang gui extract showed “weak” estrogen and

androgen antagonistic effects of 50% and 71% blocking activity,

respectively, and no progestational activity (29). In

contrast to these findings, another group of researchers

found no estrogen receptor binding, cell proliferation, or

progestin activity of an aqueous-ethanol extract of dang

gui (30).

A study of ovariectomized rats showed that an extract

of dang gui (300 mg/kg SC; 1% ligustilide) resulted

in a thickening of the luminal epithelium suggesting a

estrogenic activity, but one much lower than comparison

with estradiol. The extract also suppressed luteinizing

hormone secretion. The researchers considered ligustilide

to be the active compound on the basis of previous in vitro

research they conducted (31). Several preclinical studies

have investigated the estrogenicity of dang gui or ferulic

acid, with mixed, but largely negative, results. Some in

vitro assays have reported that dang gui extract exhibited

a significant dose-dependent inhibition of estrogen receptor

binding, indicating that it competed with estradiol

for receptor sites (32). In the same study, dang gui extract

dose-dependently induced reporter gene expression in

estrogen-sensitive rat uterine leiomyoma cells, suggesting

a potentially proliferative effect on these cells. However,

when tested in conjunction with the maximum stimulatory

dose of estradiol, the extract inhibited estradiolinduced

reporter gene expression, suggesting the possibility

that dang gui may act as an estrogen antagonist when

in the presence of physiological levels of estradiol. Another

group of researchers reported similar findings (33).

Effects on Smooth Muscle

Dang gui and its constituents have been shown to relax

the smooth muscle tissue of the vascular system, trachea,

intestines, and uterus. The spasmolytic effects of dang

gui on trachea and uterine tissues are consistent with

TCM indications. While the mechanism of the relaxant

action has not been fully elucidated, preclinical studies

suggest that it may be due, in part, to histamine receptor

blocking activity, calcium ion channel effects, or modulation

of cholinergic receptors. Both relaxing and stimulating

effects on uterine tissue have been reported, with

various constituents eliciting different actions. The therapeutic

relevance of in vitro findings to humans is unknown

given the lack of clinical evidence. Ex vivo studies

demonstrate that ligustilide and butylidenephthalide

isolated from the volatile oil of dang gui exhibit a strong

spasmolytic effect on isolated uteri (34,35). Ligustilide was

shown to relax early pregnant and nonpregnant uteri of

experimental animals (34). Ligustilide and butylidenephthalide

showed an inhibitory effect on prostaglandin F2-,

oxytocin-, or acetylcholine-induced contraction of nonpregnant

rat uteri (14,36). This could explain the spasmolytic

effect of the volatile oil. Other studies indicated

that the observed spasmolytic effect may be due to an

effect on calcium channels (14,37). Three of the available

studies reviewed found that ferulic acid elicited a uterine

spasmolytic effect. At oral doses of 300 to 1000 mg/kg

and IV doses of 30 to 300 mg/kg, ferulic acid inhibited

spontaneous uterine contraction in rats (16,17). The inhibitory

effect of IV ferulic acid was not blocked by either

propranolol or by cimetidine and it strongly inhibited the

uterine contraction induced by oxytocin (0.3 unit/kg), but

not that induced by acetylcholine (0.1 mg/kg) or serotonin

(10 g/kg). It was suggested that the uterine relaxant effect

of ferulic acid is partially due to the oxytocin receptor

system rather than its inhibitory effect on prostaglandin

biosynthesis (38). Another study, however, suggested that

ferulic acid may not be responsible for the spasmolytic

effect of dang gui, since its content in raw material is low

(approximately 0.03% to 0.06%) (39).

Hematopoietic Effects

One of the traditional applications of dang gui in TCM

is its use in the treatment of “blood vacuity,” which

closely, but not completely, corresponds to aWestern medical

diagnosis of anemia. Limited clinical and preclinical

data support this use. One proposed mechanism of action

is its reported effect in stimulating hematopoiesis.

These actions appear to be primarily associated with the

polysaccharide fraction (13,40). One study demonstrated

the hematopoietic effects to at least partially be associated

with proliferation of bone marrow mononuclear cells

through signal transduction pathways (e.g., MAPK/ERK

pathway) (41).

Antioxidant Effects

There have been numerous studies demonstrating an antioxidant

effect of dang gui and its constituents. Much of

these have focused on the antioxidant activity of ferulic

acid, which is well known for its ability to prevent lipid

peroxidation, inhibit superoxide anion radical formation,

scavenge free radicals, and protect against radiation damage

(42–44). Dang gui contains only trace amounts of ferulic

acid, so these in vitro findings cannot be extrapolated

to the use of crude dang gui preparations. There are, however,

animal studies showing that dang gui polysaccharides

have a protective effect against chemically induced

ulcerative colitis and inflammation. In one study, dang

gui polysaccharides elicited anti-inflammatory effects in

the gastrointestinal mucosa through inhibition of neutrophil

infiltration in the stomach (45). In another study,

dang gui polysaccharides (5 mg and 10 mg/mL in drinking

water) attenuated colonic lesions caused by oxidative

damage induced by 2,4-dinitrobenzene sulfonic acid in

rats in a dose-dependent manner. This action was associated

with a preservation of endogenous glutathione levels.

Other studies reported tissue-healing effects of dang

gui to be associated with ornithine carboxylase activity,

c-Myc protein expression, and epidermal growth factormediated

pathway (27,46). A follow-up study by the same

group of researchers showed that crude extract of dang gui

(50 mg/kg PO) significantly accelerated the healing of gastric

ulcers in animals and showed an anti-angiogenic activity

and a quicker restoration of mucosal synthesis and

mucosal cell proliferation (47).

Studies suggest that the antioxidant activity of dang

gui may reduce ischemia–reperfusion induced injury

(48,49), ameliorate cognitive dysfunction associated with

postischemic brain damage (49), and inhibit the damage

associated with aggregation of amyloid- peptide, suggesting

a possible use of dang gui in Alzheimer’s. These

effects were reported to be correlated with both ferulic

acid and Z-ligustilide (50).

Other studies show that dang gui provides antioxidant

protection against free radical induction of rat

adrenal medulla (PC12) cell lines (51) and suppressed

radiation-induced expression of tumor necrosis factor-

and tumor growth factor--1 (52), and prevented

doxorubicin-induced cardiotoxicity, without decreasing

the antitumor activity of the drug (53).

Wound-Healing Effects

In addition to the beneficial effects of dang gui’s

antioxidant activity on tissues noted earlier, specific

wound-healing properties have been reported. One

group of researchers found that a crude extract of dang

gui (characterization and dosage not available) significantly

accelerated epithelial cell proliferation in wounds

(27,46,54). The activity was reportedly associated with an

increase in DNA synthesis and epidermal growth factor

mRNA expression. The same researchers observed direct

wound-healing effects of dang gui crude extract, with

activity associated with increased ornithine carboxylase

activity and increased c-Myc expression. Another study

found that dang gui prevented bleomycin-induced acute

injury to rat lungs. Alveolitis and the production of malondialdehyde

were all reduced (P < 0.01 or P < 0.001), suggesting

immunomodulatory and antioxidant effects (55).

Immunomodulatory Effects and Potential

Anticancer Activity

Limited animal and in vitro studies have reported on

specific immunomodulatory effects of dang gui, including

stimulation of phagocytic activity and interleukin-2

production, and an anti-inflammatory effect. There is evidence

to suggest that the polysaccharide fraction of dang

gui may contribute to these effects. However, there is no

clinical evidence supporting these effects, and there appears

to be no direct correlation betweenTCMuse of dang

gui and immunomodulatory activity (56–58).

A new direction in investigation of the use of dang

gui is for its potential anticancer activity. Ligustilide has

been shown to have direct cytotoxic activity against several

human and animal cell lines (59–61). In the absence of

clinical and directly applicable toxicological investigation,

little emphasis should be placed on these in vitro findings.

There have, however, been a number of animal studies

suggesting immunomodulatory and anticancer activity.

In one study, n-butylidenephthalide suppressed growth

of subcutaneous rat and human brain tumors, reduced

tumor volume, and significantly prolonged survival in

treated rats. This activity was reported to be due to an

induction of cell cycle arrest and apoptosis (62). Polysaccharides

have similarly been shown to inhibit growth of

murine tumors (S180, EAC, L1210) in vivo, resulting in a

prolonged survival of treated animals. In vitro, dang gui

polysaccharides were shown to inhibit the metastasis of

human hepatocellular cancer cell lines (63).

A variety of immunomodulatory activities have

been reported for dang gui polysaccharides, including

enhanced macrophage and T cell numbers, increased

production of interleukin and interferon, improved

CD4/CD8 ratios, and a general regulation of Th1- and

Th2-related cytokines (18). Other actions reported for

polysaccharides include release of nitric oxide from

peritoneal macrophages and enhanced cellular lysosomal

enzyme activity (64,65).

Effects on Bone Cells

Dang gui is traditionally used in formulas for bone

and tendon injuries. A recent study investigated the

212 Upton

pharmacology behind this indication by testing the in

vitro effects of a 1% aqueous extract of dang gui on human

osteoprecursor cells. Cells were incubated for five

days in medium with (12.5–1000 g/mL) and without

the extract. Compared to untreated control cell cultures,

cell proliferation was enhanced at extract concentrations

less than 125 g/mL (P < 0.05), whereas it was inhibited

at concentrations greater than 250 g/mL (P < 0.05

at 1 mg/mL). Protein secretion in osteoprecursor cells

and type-I collagen synthesis were significantly increased

(P < 0.05) (66).

dong quai CLINICAL STUDIES

The clinical data regarding the use of dang gui alone are

scarce and of poor methodological quality.

Cardiovascular and Hemorheological Effects

One study reported that 0.08 g/day/IV of sodium ferulate

relieved symptoms of angina pectoris after three

to seven days of treatment (24). Limited clinical studies

have investigated the use of dang gui for the treatment

of patients with acute ischemic stroke or COPD with pulmonary

hypertension. Results provide fairly weak evidence

that dang gui exerts hypotensive and cardioprotective

effects. In general, the study design of the available

reports was poor and the patient populations extremely

limited.

One study looked at the effects of dang gui in 60

patients with COPD (67). In the dang gui group, levels of

blood endothelin-1, angiotensin II, endogenous digitalislike

factor, mean pulmonary arterial pressure, and pulmonary

vascular resistance were decreased significantly

(P < 0.05 or P < 0.01) compared to those in the controls

(20 °æ 6%, 36 °æ 9%, 38 °æ 11%, 17 °æ 5%, and 27 °æ 8%,

respectively). Another study showed that dang gui decreased

the mean pulmonary arterial pressure in patients

with COPD without changing blood pressure and heart

rate, suggesting a vasodilatory effect on pulmonary vessels

without effect on systemic circulation (3).

In another study, it was suggested that dang gui

and dextran exhibited positive effects on neurological and

hemorheological symptoms in patients recovering from

stroke (68). However, no control group was included,

and so any claimed effects are questionable. Other clinical

studies with very small numbers of patients (11,69)

have reported on an ability of dang gui to decrease blood

viscosity, an effect consistent with its traditional use. While

this effect may be real, the mechanisms by which this may

occur and the constituents involved have not been well

articulated.

Hepatoprotective Effects

There is some evidence to suggest that dang gui and its

constituents can decrease portal hypertension in patients

with liver cirrhosis without affecting systemic hemodynamics.

This use is consistent with the traditional actions

of dang gui in improving circulation, because portal hypertension

is thought to be due to the obstruction of hepatic

microcirculation (70,71).

Hormonal Effects and Effects on Menopausal Symptoms

Because of the putative effects of dang gui in gynecological

imbalances, various studies have investigated its

potential for eliciting hormonal effects. In one human

study (72), one of the few double-blind, placebo-controlled

trials with dang gui, no statistically significant differences

in endometrial thickness, vaginal cell maturation, or

menopausal symptoms were observed between subjects

taking dang gui and those taking placebo. This contrasts

with a study of ovariectomized rats which showed that an

extract of dang gui (300 mg/kg SC;1%ligustilide) resulted

in a thickening of the luminal epithelium suggesting estrogenic

activity, but one much lower than comparison with

estradiol (see gynecological effects).

Analgesic Effects

Two uncontrolled clinical trials were found that addressed

the traditional Chinese use of dang gui as an analgesic for

pain due to “blood stasis”; both used injectable preparations.

In one, an ethanol extract was administered (intramuscularly)

on alternate days for a total of 20 doses into

the pterygoideus externus of 50 patients with temporomandibular

joint syndrome. A 90% cure rate was claimed

(73). Thirty cases of refractory interspinal ligament injury

were treated by local injection of 2 mL of 5% or 10% dang

gui twice weekly for two to three weeks. Twenty-four

(80%) of these patients reported a disappearance of pain,

no tenderness, and the ability to work as usual; four (13%)

patients reported alleviation of pain; two (7%) reported

no improvement (74). These uses are consistent with the

traditional use of dang gui in TCM. However, the effects

of injectable preparations cannot be extrapolated to oral

use of dang gui.

Dosages

Crude herb: 6 to 12 g daily to be prepared as a decoction.

Fluid extract (1:1): 3 to 5 mL three times daily (75).

SAFETY PROFILE

Side Effects

On the basis of a review of the available traditional and

scientific data, dang gui is a very safe herb with a low

probability of side effects when used within its normal

dosage range. One review article that claimed to cover

200 reports on dang gui pharmacology stated that dang

gui had no major side effects (35). Individual case reports

regarding the potential of dang gui to promote bleeding

have been prepared.

Contraindications

On the basis of a review of the available literature and the

experience of practitioners, dang gui is contraindicated

prior to surgery and, generally speaking, in those with

bleeding disorders.

Precautions

Precautions regarding the use of dang gui and other botanicals

used in traditional systems of medicine must be differentiated

between those recognized in the scientific literature

and those recognized traditionally. There is evidence

suggesting an anticoagulant effect for dang gui, and there

Dong Quai 213

are two published reports on its ability to enhance the

effects of chronic treatment with warfarin (see interactions).

A few unpublished case reports suggest that high

doses or chronic administration of dang gui alone during

pregnancy may be associated with miscarriage. There are

also anecdotal reports of administration of dang gui alone

causing increased blood flow during menses (R.U., personal

communication). Therefore, patients should consult

with a qualified health care professional prior to using

dang gui if they have bleeding disorders, are using anticoagulant

medications, or wish to use it during menses

or in the first trimester of pregnancy. It must, however, be

noted that in TCM, dang gui is specifically indicated for

certain bleeding disorders that are due to an underlying

diagnosis of blood stasis and in certain cases of threatened

miscarriage. For such uses, dang gui must be used according

to TCM principles under the guidance of a qualified

TCM practitioner.

Interactions

Two reports are available suggesting that dang gui can enhance

the effects of the anticoagulant warfarin. According

to one of these, a 46-year-old woman with atrial fibrillation

who had been stabilized on warfarin for almost two

years (5 mg daily) consumed a dang gui product concurrently

for four weeks (565–1130 mg daily). She experienced

a greater than twofold elevation in prothrombin

time (from 16.2 to 27 sec) and international normalized

ratio (from 2.3 to 4.9). No other cause for this increase

could be determined. Within one month of discontinuing

dang gui use, coagulation values returned to acceptable

levels (76).

Ananimal study investigated the interaction of dang

gui and a single dose or a steady-state dose of warfarin

(77). Six rabbits were administered a single dose of warfarin

(2 mg/kg SC). Seven days later, the same animals

were given an aqueous extract of dang gui (2 g/kg PO,

twice of a 2 g/mL extract daily) for three days, after which

they were again given a single dose of warfarin. Plasma

warfarin concentrations were measured at intervals up to

72 hour after each warfarin dose, and prothrombin time

was measured daily during dang gui treatment and after

the warfarin doses. Mean prothrombin time did not

change significantly during the dang gui treatment period.

However, when measured after coadministration of dang

gui and warfarin, prothrombin time was significantly lowered

at 24, 36, and 48 hours compared to that with warfarin

treatment alone (P < 0.05 or P < 0.01). No significant

variations in the single dose pharmacokinetic parameters

of warfarin were observed after treatment with

dang gui. Hence, the mechanism of decrease in prothrombin

time could not be correlated to the pharmacokinetics

of warfarin. Another group of six rabbits was given 0.6

mg/kg of warfarin SC daily for seven days; a steadystate

plasma concentration was achieved after day 4. On

days 4, 5, and 6, the rabbits were treated as above with

dang gui. Mean prothrombin time was again significantly

increased after coadministration with dang gui and two

rabbits died at days 6 and 7 after the dang gui treatment

had begun. Plasma warfarin levels did not change after

dang gui treatment. The authors suggested that these results

indicate that precautionary advice should be given

to patients who medicate with dang gui or its products

while on chronic treatment with warfarin. Another

study reported that dang gui acted synergistically with

aspirin (24).

General enhancement of cytochrome P450 isoforms

has been reported for both water (CYP2D6 AND 3A)

and ethanol extracts (CYP2D6) of dang gui in animal

models (78).

One study reported that dang gui might enhance

the antitumor effect of cyclophosphamide in mice with

transplanted tumors (79).

Pregnancy, Mutagenicity, and Reproductive Toxicity

Because of its blood-moving properties, dang gui should

be used in pregnancy only under the supervised care of

a qualified health professional. According to TCM practice,

dang gui is used in combination with other herbs in

various stages of pregnancy (29). Formula traditionally

used in pregnancy are prescribed within the context of

specific diagnoses in which the use of dang gui in pregnancy

is clearly indicated. In the West, dang gui is often

used alone out of this traditional medical context. Because

of this, several Western sources consider dang gui to be

contraindicated in pregnancy. Data regarding the effect of

dang gui preparations on the fetus are lacking.

Lactation

There are three unpublished case reports of a rash in infants

of lactating mothers who were taking dang gui. The

rashes reportedly resolved upon discontinuation of the

preparation by the mother. Specific details regarding

the preparations used were lacking (Romm, August 1,

2002, oral communication to AHP). Dang gui is a member

of the botanical family Apiaceae, a group of plants that

contain many types of photoreactive compounds known

to cause rashes.

Carcinogenicity

Data regarding the effects of dang gui in relationship to

carcinogenicity are mixed with both tumorigenic and antitumorigenic

activity reported. Antitumor activity due to

an induction of cell cycle arrest and apoptosis has been

reported for ligustilide (62). Polysaccharides have been

shown to inhibit growth of murine tumors (S180, EAC,

L1210) in vivo. This was accompanied by a prolonged

survival of animals and an inhibition of metastasis in vitro

(63). Another animal study identified a possible antitumor

effect of dang gui applied to mice with Ehrlich ascites tumors

(80). Regarding the potential effects of dang gui on

estrogen-positive tumors the data are mixed. One in vitro

assay found that dang gui stimulated the growth of MCF-

7 breast cancer cell lines 16-fold, with no measurable effect

on estrogen receptors (81), while another found a possible

antitumor effect in T-47D and MCF-7 cell lines (82). Data

regarding the potential estrogenic effects of dang gui have

been mixed.

Influence on Driving

On the basis of the experience of modern herbal practitioners,

no negative effects are to be expected.

Overdose

On the basis of the available literature, its use as a “food”

ingredient in soups, and the experience of modern herbal

practitioners, dang gui appears to be safe when used at

recommended doses.

Treatment of Overdose

No data available.

Toxicology

The following lethal dose (LD50) values have been reported

for dang gui extract (8:1 or 16:1), 100 g/kg PO in

rats (83,84); dang gui aqueous extract, 100 g/kg IV in mice

(85); dang gui 50% ethanol extract, greater than 40 g/kg

PO in mice (86); dang gui total acids, 1.05°æ0.49 g/kg IP in

mice (87). The LD50 of ferulic acid IV in mice was reported

to be 856.6 mg/kg, (16) and that of ligustilide, approximately

410 mg/kg IP (88). In a review of the toxicology

literature on dang gui, it was reported that IV injection

of the volatile fraction of dang gui could cause kidney

degeneration (76).

REGULATORY STATUS

Regulated as a dietary supplement (USC 1994).

CONCLUSIONS

Dang gui is one of the most important herbal drugs in

TCM, primarily being used for blood tonification and the

treatment of gynecological disorders. More recently, interest

has focused on dang gui’s possible cardiovascular, hepatoprotective,

hematopoietic, antioxidant, antispasmodic,

and immunomodulatory effects. Despite its long tradition

of use and current widespread clinical utility, there has

been very little clinical work verifying the therapeutic efficacy

of dang gui when used alone, primarily due to the

fact that in TCM, botanicals are generally used in combinations

rather than as single agents.

On the basis of the literature available and keeping

many of its limitations for an English readership in

mind, there is limited clinical support for the use of dang

gui alone for the following indications: pulmonary artery

and portal hypertension, acute ischemic stroke, dysmenorrhea,

infertility, and pain due to injury or trauma. The

use of dang gui for most of these indications is consistent

with TCM. One trial on menopausal symptoms found no

effect of dang gui on hormonal activity. Most of the trials

available are of poor methodological quality.

Clinical and preclinical studies provide some

support for a wide variety of actions of dang gui.

These include the promotion of circulation, vasodilation/

relaxation, and the inhibition of platelet aggregation,

all of which are consistent with the “blood quickening”

properties ascribed to dang gui in TCM. Similarly, the

hematopoietic effect of dang gui is consistent with its use

in TCM to “nourish blood.” Its smooth muscle (uterus,

vessels, trachea) relaxant effects are consistent with its use

for dysmenorrhea, asthma, and coughing. Dang gui may

relax or stimulate the uterus depending on a variety of

factors. In general, the volatile oil fraction appears to be

a uterine relaxant, while the nonvolatile constituents appear

to stimulate contractions. There is some support for

the traditional use of dang gui as an analgesic and vulnerary.

The radiation protective effect of dang gui in animals

is most likely due to its antioxidant activity. Assays for an

estrogenic effect of dang gui have had mixed, but largely

negative, results. The relevance of many of these actions

to the therapeutic use of dang gui in humans has not yet

been demonstrated.