How long does it take for black cohosh to work?


Black Cohosh: Uses, Benefits, and Side Effects

Black cohosh is a flowering plant. It grows in parts of the United States and Canada.

The perennial produces white flowers from June to September, but it gets its name from its black roots. The roots are believed to have healing properties.

The black cohosh root has a long history of being used to treat medical conditions. Native Americans used black cohosh in a wide variety of ways, including:

  • kidney issues
  • malaria
  • rheumatoid arthritis
  • joint inflammation
  • sore throat
  • helping with labor
  • menstrual cramps
  • menopause

Early American colonists used black cohosh to treat snake bites, uterus issues, nervous disorders, and more. Black cohosh was also an ingredient in Lydia Pinkham’s Vegetable Compound, an herbal menstrual cramp remedy popular in the early 1900s.

Today, black cohosh is mainly used to help treat symptoms associated with menopause. Read on to learn more about how it’s used and the potential side effects.

How is black cohosh used?

The roots of black cohosh are dried and made into teas, liquid extracts, and put into capsule form. Sometimes, black cohosh is used as one ingredient in an herbal mixture.

Remifemin is an example. It’s a mixture that’s been sold as a menopause tablet for 40 years in Europe. It contains 20 milligrams (mg) of black cohosh extract.

You can buy supplements with black cohosh as a concentrated liquid, in pill form, or as part of an herbal combination formula. It’s available in most drug stores or online.

There’s no standardized dose for the herb. Extracts and mixtures can vary in the amount they contain. Generally, 20 to 40 mg is used to treat menopause symptoms.

What are the benefits of black cohosh?

The most widely studied treatment use of black cohosh has been for hot flashes and other menopause symptoms. But research is still mixed as to whether it’s effective or not.

Some studies say it does help reduce hot flashes and improves mood and sleep patterns for women during menopause. Other research has shown the herb to be ineffective.

Experts aren’t sure exactly how black cohosh works or why it might be helpful for menopause symptoms. One theory is that it may have estrogenic activity, though this has not panned out in studies. For this reason, it’s possible that black cohosh is harmful for women going through treatment for breast cancer, at least for estrogen-positive tumors.

What does research say about the effectiveness of black cohosh?

Studies funded by the National Center for Complementary and Integrative Health reported conflicting findings regarding the effectiveness of black cohosh used alone or in combination with other herbs in reducing hot flashes and/or night sweats. Women in the study were premenopausal or menopausal.

One recent study in the International Journal of Reproductive Biomedicine found black cohosh, along with a few other herbs used in Iranian medicine, to be an effective alternative treatment for women experiencing hot flashes.

Most of the clinical studies have focused on treating menopause symptoms. The women in the studies have only been evaluated for about six months. For this reason, the current American College of Obstetrics and Gynecology guidelines on herbs as treatment for menopause support only using black cohosh for six months or less.

What are the side effects of black cohosh?

Black cohosh is associated with generally mild side effects, though some are more serious than others. One of the major side effects is liver damage.

Don’t use black cohosh if you have a history of liver disorders. Also avoid it if you’re experiencing symptoms that can signal liver trouble, like abdominal pain, jaundice, or dark-colored urine.

Other side effects of black cohosh include:

  • upset stomach
  • dizziness
  • headache
  • nausea
  • vomiting
  • low blood pressure
  • changes in heart rhythm

The black cohosh plant is in the same family as the buttercup plant, so people who have allergies to buttercups should not try black cohosh.

Black cohosh isn’t recommended for use during pregnancy or breast-feeding. There’s a risk of causing early labor for women who are pregnant. It’s not yet known if the herb is safe for breast-feeding women. It is also not recommended for use in children.

Other considerations when using black cohosh

Herbs, vitamins, minerals, and other plant extracts are considered dietary supplements. These aren’t required to be regulated by the Food and Drug Administration (FDA). That means these products don’t have to meet standards set by the FDA the way medications and food do.

It’s possible for manufacturers to make misleading claims about the product’s effectiveness. The ingredients can also vary. In some cases, particularly with mixtures, the supplement might not contain what it claims to.

Before buying dietary supplements, check to see if the supplement maker has a large amount of negative reviews or outstanding lawsuits. Buy only from good, reputable sources.

Herbs have the potential to interact with other medications, so you should always talk to your doctor about adding supplements to your treatment plan.

Next steps

There’s some evidence that black cohosh can help treat hot flashes. But experts don’t know enough to say for sure if it will offer relief from menopausal symptoms. It’s likely a safe alternative treatment if used for six months or less.

If you’re considering trying the herb, first talk to your doctor. Taking black cohosh might help, but it’s not a substitute for any recommended treatments.

Estroven Caplets

What is Estroven?

Estroven is a dietary supplement containing natural ingredients. Estroven helps reduce physical and psychological effects of hormonal imbalance associated with perimenopause, menopause and postmenopause.

Estroven Uses

Clinical studies of the specific ingredients in Estroven when used by women experiencing early climacteric symptoms (perimenopause) have shown significant reduction in vasomotor symptoms including night sweats and hot flashes; reduction of hormone-related irritability; support for a restful sleep; and protective effects on bones and the cardiovascular system.*

Estroven Directions

Take one caplet daily a few hours before bedtime with food.

Estroven contains a natural calming herbal blend that, when taken before retiring for the day, may help you relax, enjoy a good night’s sleep and have an energized morning.*

It is recommended that all supplements be taken with food to avoid any minor stomach upset that may result when supplements are taken on an empty stomach. Additionally, some nutrients such as vitamin E and the B vitamins are better absorbed with food.

Estroven Precautions

Do not take if pregnant, breastfeeding, or trying to conceive. Keep out of reach of children.

Estroven Adverse Reactions

There are no major side effects associated with the recommended dosage of Estroven.


Each caplet contains: Vitamin E 30IU; Thiamin 2mg; Riboflavin 2mg; Niacin 20mg; Vitamin B-6 10mg; Folate 400mcg; Vitamin B-12 6mcg; Calcium 150mg; Selenium 70mcg; Estroven Calming Herbal Blend (proprietary blend of Date seed extract and Magnolia bark extract) 150mg; Isoflavones (from Pueraria lobata root extract and GMO-free soybeans) 55mg; Black cohosh root standardized extract 40mg, Boron 1.5mg.

Estroven helps to naturally support hormonal balance with ingredients known to be good sources of phytoestrogens. Phytoestrogens are naturally occurring compounds found in many plants including soybeans, whole grain cereals, seeds, nuts and many herbs. Phytoestrogens have a structure similar to that of the estrogen produced in your body and help support hormonal balance.* Studies have shown that women who consume foods high in phytoestrogens experience less dramatic hormone fluctuations during menopause.*

Soy Isoflavones
Soybeans are very rich sources of phytoestrogens called isoflavones. The specific plant estrogens in soy include daidzein and genistein.

Standardized Black Cohosh
Black cohosh is a rich herbal source of natural phytoestrogens that has been clinically shown to reduce hot flashes.* It has been used for centuries throughout the world to provide support for many areas of female health.

Calcium and Boron
Estroven is a good source of supplemental calcium to support strong bones.* Boron is an essential nutrient which aids calcium absorption.*

Natural Vitamin E, B-12, B-6 and Folic Acid
Vitamins E, B-6, B-12 and folic acid have been extensively researched, and all play an integral role in supporting cardiovascular health.*

Estroven Calming Herbal Blend
A natural blend of traditional herbs used to reduce irritability and get a good night’s sleep.*

B Vitamins
Thiamin (B-1), riboflavin (B-2), and niacin (B-3) work together to transform carbohydrates in your diet into energy.*

Other Ingredients – cellulose, croscarmellose sodium, silica, vegetable magnesium stearate, titanium dioxide (natural mineral source), vanilla and caramel color.

Estroven contains no artificial dyes, colors, preservatives, flavors, yeast, wheat, gluten or lactose.

* These statements have not been evaluated by the FDA. Estroven is not intended to diagnose, treat, cure or prevent any disease.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer

Hot Flashes: What Can I Do?

Hot flashes, a common symptom of the menopausal transition, are uncomfortable and can last for many years. When they happen at night, hot flashes are called night sweats. Some women find that hot flashes interrupt their daily lives. The earlier in life hot flashes begin, the longer you may experience them. Research has found that African American and Hispanic women get hot flashes for more years than white and Asian women.

You may decide you don’t need to change your lifestyle or investigate treatment options because your symptoms are mild. But, if you are bothered by hot flashes, there are some steps you can take. Try to take note of what triggers your hot flashes and how much they bother you. This can help you make better decisions about managing your symptoms.

Lifestyle Changes to Improve Hot Flashes

Before considering medication, first try making changes to your lifestyle. Doctors recommend women make changes like these for at least 3 months before starting any medication.

If hot flashes are keeping you up at night, keep your bedroom cooler and try drinking small amounts of cold water before bed. Layer your bedding so it can be adjusted as needed. Some women find a device called a bed fan helpful. Here are some other lifestyle changes you can make:

  • Dress in layers, which can be removed at the start of a hot flash.
  • Carry a portable fan to use when a hot flash strikes.
  • Avoid alcohol, spicy foods, and caffeine. These can make menopausal symptoms worse.
  • If you smoke, try to quit, not only for menopausal symptoms, but for your overall health.
  • Try to maintain a healthy weight. Women who are overweight or obese may experience more frequent and severe hot flashes.
  • Try mind-body practices like yoga or other self-calming techniques. Early-stage research has shown that mindfulness meditation, yoga, and tai chi may help improve menopausal symptoms.

Medications: Non-Hormone Options for Treating Hot Flashes

If lifestyle changes are not enough to improve your symptoms, non-hormone options for managing hot flashes may work for you. They may be a good choice if you are unable to take hormones or if you are worried about their potential risks.

The U.S. Food and Drug Administration (FDA) has approved the use of paroxetine, a low-dose selective serotonin reuptake inhibitor (SSRI) antidepressant, to treat hot flashes. Researchers are studying the effectiveness of other antidepressants in this class.

Women who use an antidepressant to help manage hot flashes generally take a lower dose than people who use the medication to treat depression. Side effects depend on the type of antidepressant you take and can include dizziness, headache, nausea, jitteriness, or drowsiness. As with any medication, talk with your doctor about whether this is the right medication for you and how you can manage any possible side effects.

Medications: Treating Hot Flashes and Night Sweats with Hormones

Some women may choose to take hormones to treat their hot flashes. A hormone is a chemical substance made by an organ like the thyroid gland or ovary. During the menopausal transition, the ovaries begin to work less and less well, and the production of hormones like estrogen and progesterone declines over time. It is believed that such changes cause hot flashes and other menopausal symptoms.

Hormone therapy steadies the levels of estrogen and progesterone in the body. It is a very effective treatment for hot flashes in women who are able to use it. There are risks associated with taking hormones, including increased risk of heart attack, stroke, blood clots, breast cancer, gallbladder disease, and dementia. The risks vary by a woman’s age and whether she has had a hysterectomy. Women are encouraged to discuss the risks with their healthcare provider.

Women who still have a uterus should take estrogen combined with progesterone or another therapy to protect the uterus. Progesterone is added to estrogen to protect the uterus against cancer, but it also seems to increase the risk of blood clots and stroke. Hormones should be used at the lowest dose that is effective for the shortest period of time possible. (See What Are the Risks of Using Hormones for Hot Flashes?)

Some women should not use hormones for their hot flashes. You should not take hormones for menopausal symptoms if:

  • You have had certain kinds of cancers, like breast cancer or uterine cancer
  • You have had a stroke or heart attack, or you have a strong family history of stroke or heart disease
  • You have had blood clots
  • You have had problems with vaginal bleeding or have a bleeding disorder
  • You have liver disease
  • You think you are pregnant or may become pregnant
  • You have had allergic reactions to hormone medications

Talk with your doctor to find out if taking hormones to treat your symptoms is right for you.

Should I Take Hormones for My Hot Flashes?

Share this infographic and help spread the word about things women can do to stay healthy after menopause.

Talk with your doctor before using hormones to treat menopause symptoms. Hormones should be used at the lowest dose and for the shortest period of time they are effective.

Hormones can be very effective at reducing the number and severity of hot flashes. They are also effective in reducing vaginal dryness and bone loss.

Hormone treatments (sometimes called menopausal hormone therapy) can take the form of pills, patches, rings, implants, gels, or creams. Patches, which stick to the skin, may be best for women with cardiac risk factors, such as a family history of heart disease.

There are many types of hormones available for women to treat hot flashes. These include estradiol, conjugated estrogen, selective estrogen receptor modulators (SERMs), and compounded or synthetic hormones. It is a common misconception that synthetic (“bioidentical”) hormones mixed by a compounding pharmacist are safer and less risky than other hormone therapies. This is not the case. We must assume they have the same risks as any hormone therapy.

Some of the relatively mild side effects of hormone use include breast tenderness, spotting or return of monthly periods, cramping, or bloating. By changing the type or amount of the hormones, the way they are taken, or the timing of the doses, your doctor may be able to help control these side effects or, over time, they may go away on their own.

What Are the Risks of Using Hormones for Hot Flashes?

In 2002, a study that was part of the Women’s Health Initiative (WHI), funded by the National Institutes of Health, was stopped early because participants who received a certain kind of estrogen with progesterone were found to have a significantly higher risk of stroke, heart attacks, breast cancer, dementia, urinary incontinence, and gallbladder disease.

This study raised significant concerns at the time and left many women wary of using hormones.

However, research reported since then found that younger women may be at less risk and have more potential benefits than was suggested by the WHI study. The negative effects of the WHI hormone treatments mostly affected women who were over age 60 and post-menopausal. Newer versions of treatments developed since 2002 may reduce the risks of using hormones for women experiencing the menopausal transition, but studies are needed to evaluate the long-term safety of these newer treatments.

If you use hormone therapy, it should be at the lowest dose, for the shortest period of time it remains effective, and in consultation with a doctor. Talk with your doctor about your medical and family history and any concerns or questions about taking hormones.

Buyer Beware: Unproven, Nonscientific “Treatments” for Hot Flashes

You may have heard about black cohosh, DHEA, or soy isoflavones from friends who are using them to try to treat their hot flashes. These products are not proven to be effective, and some carry risks like liver damage.

Phytoestrogens are estrogen-like substances found in some cereals, vegetables, and legumes (like soy), and herbs. They might work in the body like a weak form of estrogen, but they have not been consistently shown to be effective in research studies, and their long-term safety is unclear.

At this time, it is unknown whether herbs or other “natural” products are helpful or safe. The benefits and risks are still being studied. Always talk with your doctor before taking any herb or supplement to treat your hot flashes or other menopausal symptoms.

Other Menopause Symptoms and Treatments

For most women, hot flashes and trouble sleeping are the biggest problems associated with menopause. But, some women have other symptoms, such as irritability and mood swings, anxiety and depression, headaches, and even heart palpitations. Many of these problems, like mood swings and depression, are often improved by getting a better night’s sleep. Discussing mood issues with your doctor can help you identify the cause, screen for severe depression, and choose the most appropriate intervention. For depression, your doctor may prescribe an antidepressant medication.

If you want to change your lifestyle to see if you can reduce your symptoms, or if you decide any of your symptoms are severe enough to need treatment, talk with your doctor.

Treating Menopause Symptoms: What’s Right for Me?

Deciding whether and how to treat the symptoms of the menopausal transition can be complicated and personal. Discuss your symptoms, family and medical history, and preferences with your doctor.

No matter what you decide, see your doctor every year to talk about your treatment plan and discuss any changes you want to make.

Learn more about the signs and symptoms of menopause, as well as tips to help you get a better night’s sleep during the menopausal transition.

Read about this topic in Spanish. Lea sobre este tema en español.

For More Information on Treatments for Hot Flashes

National Institutes of Health Menopausal Hormone Therapy Information

North American Menopause Society

This content is provided by the National Institute on Aging (NIA), part of the National Institutes of Health. NIA scientists and other experts review this content to ensure that it is accurate, authoritative, and up to date.

Content reviewed: June 26, 2017

Sleep boosting supplements that also help with menopause

Treating sleep disruptions and menopause symptoms naturally

So many women I talk to want to treat their sleep problems as naturally as possible. I’m on board with that idea! Lifestyle and behavioral changes, including diet, exercise, mind-body therapies, relaxation exercises and stress management are the foundation of healthy, lifelong sleep hygiene. For many women, supplements can also play a tremendously beneficial role in improving sleep.

The same goes for managing menopause symptoms. The good news is that many of the most well-studied and effective supplements for sleep problems also can help women find relief from menopausal symptoms, and move through the menopause transition feeling, thinking, and performing their best.

Here, I’ll talk about some of the best sleep-promoting supplements—and how they can also address menopause symptoms.

A decision to use supplements should be made in consultation with your physician, taking into account your individual health history and risks. This is not medical advice, but I hope this discussion will give women a starting point for those conversations with their physicians about natural therapies to improve their sleep, protect their health, and reduce their uncomfortable symptoms during menopause.

When you talk to your doctor, be sure to discuss any supplements you’re considering and review potential interactions with any medications or other supplements you’re already using.

Melatonin: the go-to sleep hormone
Most women know melatonin as a go-to supplement for sleep. But a lot of women don’t know that melatonin can treat other symptoms of menopause. I wrote recently about the broad spectrum of benefits melatonin has for sleep, cardiovascular and cognitive health, as well as other health benefits.

Many people think melatonin works as a sedative—but it doesn’t. Melatonin—whether produced by your body or ingested as a supplement – improves sleep by helping the body better regulate its biological clock and sleep-wake cycles. Melatonin can help to strengthen and improve sleep-wake cycles, making it easier to sleep on a regular schedule. Melatonin can also shorten the time it takes to fall asleep, and increase overall sleep amounts. Higher levels of melatonin also may improve the quality of sleep and reduce daytime sleepiness and fatigue, as well as increasing REM sleep.

Melatonin has strong antioxidant powers—and that means it can help protect against cell damage in the brain and throughout the body. Recent research shows that melatonin may exert its protective, antioxidant effect over neural cells, helping to delay or prevent cognitive impairment and memory loss. Women’s risks for cognitive decline increase as they age and move through menopause.

There’s also evidence that melatonin can strengthen aging bones. Scientists have recently identified melatonin as a promising therapy to prevent and to treat osteoporosis. The decline in estrogen and other hormones that happens during menopause increase women’s risk for bone loss and osteoporosis.

Here’s some important information to know, when considering using a melatonin supplement: Recent research found that the actual melatonin content found in many supplements on the market may vary significantly from what product labels claim. Scientists at Ontario’s University of Guelph found that in more than 71 percent of melatonin supplements, the amount of melatonin was more than 10 percent different from what the product label indicated. Some products contained as much as 83 percent less melatonin, while other products contained as much as 478 percent more melatonin. That means a great many consumers aren’t getting the doses they think they are. Before you begin using melatonin, be sure to do your research and get your melatonin from a trusted source.

Magnolia bark: the ancient sleep booster and stress beater

The magnolia plant has an ancient history as a therapeutic compound in traditional Chinese, Japanese, and Korean medicine, used to promote sleep and relaxation, to ease anxiety, and to treat allergies and asthma, among other conditions. (I’ll be sharing a full profile of the therapeutic powers of magnolia bark soon, so check back to learn all about the benefits of this supplement.)

Research shows the bioactive compounds in magnolia bark can reduce the time it takes you to fall asleep, and can increase the amount of time you spend in both REM sleep and NREM sleep. Magnolia lowers levels of adrenaline, making it an effective natural sleep aid for people who tend to be wired or stressed.

Magnolia bark can be highly effective as a stress-reliever and anxiety-soother. Research indicates that one of the active compounds in magnolia bark—honokiol—works as effectively as the drug diazepam to treat anxiety, without the same risks of dependency or side effects. Women going through menopause often experienced heightened stress as well as anxiety and depression, which can interfere with quality of life, daily performance, and relationships.

Magnolia bark affects the activity of both serotonin and dopamine, two neurotransmitters that are important to mood. Research indicates that magnolia can help with depression, both on its own and in combination with ginger. Research shows specifically that magnolia bark helps improve sleep and relieve mood problems in women undergoing menopause.

Magnolia bark’s bioactive compounds can help maintain levels of acetylcholine, a neurotransmitter that helps the brain process memory and learning.

Weight gain is a common problem and concern for women undergoing menopause. Research shows compounds in magnolia bark extract may help guard against weight gain and decrease body fat. Studies also indicate magnolia bark can improve insulin resistance, and contribute to reductions in triglycerides and cholesterol. Estrogen

Magnolia bark has long been used in traditional and natural medicine for as an anti-inflammatory and a source of pain relief, and has been used to help alleviate joint and muscle pain, as well as headache and menstrual cramps. Research in mice shows magnolia bark can be effective in reducing pain caused by inflammation.

L-Theanine: the ‘wakeful relaxation’ enhancer

L-theanine is an amino acid that is found in tea leaves. I’m a fan of this supplement for its ability to improve sleep and promote relaxation without making you feel sleepy during the day. I wrote full rundown on the science and the potential benefits of L-theanine to sleep and health—read it here.

It’s benefits for sleep? L-theanine may help people fall asleep more quickly and easily at bedtime, thanks to the relaxation boost it delivers. Research also shows L-theanine can improve the quality of sleep—not by acting as a sedative, but by lowering anxiety.

L-theanine elevates levels of GABA, as well as serotonin and dopamine. These chemicals are known as neurotransmitters, and they work in the brain to regulate emotions, mood, concentration, alertness, and sleep, as well as appetite, and energy. Increasing levels of these calming brain chemicals not only helps sleep, but may provide relief for women experiencing mood swings, difficulty concentrating, and changes to appetite during menopause.

At the same time, it is increasing chemicals that promote feelings of calm, L-theanine also reduces levels of chemicals in the brain that are linked to stress and anxiety. This may also be a way that L-theanine can protect brain cells against stress and age-related damage. L-theanine has positive effects on both the mental and physical symptoms of stress, including lowering heart rate and blood pressure.

Under stress, the body increases production of certain hormones, including cortisol and corticosterone. These hormone changes inhibit some brain activity, including memory formation and spatial learning. L-theanine helps to lower levels of the stress hormonecorticosterone, and avoid the interference with memory and learning.

L-theanine may also play a more direct role in weight maintenance. There’s scientific evidence indicating L-theanine may help to limit fat accumulation and weight gain, and pay help to protect against obesity.

Magnesium: the vital-for-sleep-and-everything-else mineral

Magnesium is about as close as you can get to an all-around sleep and health supplement. Because of its role as an enabler of healthy enzyme function, magnesium plays an important part in most of our physiological functions. Check out the details on the whole spectrum of benefits magnesium can deliver.

Helpful to pre-menstrual women in relieving symptoms of PMS –including mood swings, irritability, anxiety and tension, and bloating – magnesium also can make a big difference to women in menopause. One of the seven essential macro-minerals that the human body needs in large quantities, maintaining healthy magnesium levels protect metabolic health, stabilize mood, keep stress in check, promote better sleep, and contribute to heart and bone health.

Magnesium deficiency is common, with nearly half of adult men and women in the United States are likely deficient in magnesium. Older adults are more vulnerable to magnesium deficiency. Women are also at higher risk for low magnesium, especially with age.

Keeping magnesium levels healthy can lead to deeper, more sound sleep. Research indicates supplemental magnesium can improve sleep quality, especially in people with poor sleep.

Supplemental magnesium has been shown to have a stabilizing effect on mood. This whole-health mineral has been shown effective in relieving symptoms of both mild-to-moderate anxiety and mild-to-moderate depression.

Magnesium plays a critical role in maintaining bone density. It helps the body effectively use the building blocks of strong bones, including the nutrients calcium and Vitamin D. The role of magnesium to bone health becomes increasingly important with age. Higher magnesium intake is linked to greater bone density in women. In postmenopausal women, magnesium has been shown to improve bone mass.

Another benefit for women in menopause, especially those with sleep problems and physical pain? Magnesium helps to relax muscles, and soothe muscle and joint pain.

5-HTP: the mood-and-sleep hormone elevator

This one has a funny sounding name, but it can do a lot for sleep as well as for mood, and to help regulate appetite.

5-Hydroxytryptophan—commonly known as 5-HTP—is a compound made naturally in the body. 5-HTP is created as a by-product of the amino acid L-tryptophan. Our bodies don’t make L-tryptophan naturally—we absorb this essential amino acid from the foods we eat. As we age, natural levels of 5-HTP appear to decline.

5-HTP helps the body to produce more serotonin. Serotonin is a neurotransmitter that plays a key role in regulating mood and sleep-wake cycles. Healthy levels of serotonin contribute to a positive mood and outlook and also promote restful sleep. Serotonin also plays an important role in many other of the body’s functions, including digestion, appetite, and pain perception.

Because of its role in creating serotonin, 5-HTP is indirectly involved in producing melatonin, a hormone that is critical for sleep.

Because of its serotonin-boosting capability, 5-HTP may also help with other conditions, including mood problems, stress, pain, and appetite control. Low serotonin may also trigger hot flashes—keeping serotonin levels up may help reduce a woman’s risk for hot flashes.

5-HTP has been shown in scientific studies to promote relaxation and alleviate stress and anxiety. Research also indicates 5-HTP may be effective in helping to alleviate depression.

5-HTP has been recognized as important to appetite regulation. Higher levels of serotonin are linked to diminished appetite. Keeping serotonin levels from dipping can help keep appetite in check, and may help reduce cravings for carbohydrates. As a serotonin booster, 5-HTP may help to suppress appetite. Research indicates that 5-HTP may be effective in helping people who are overweight or obese lose weight.

Scientific evidence shows 5-HTP may be able to reduce the frequency of migraine headache attacks and reduce pain from chronic headaches. Many women experience headache and migraine during menopause.

Want to learn more about 5-HTP? I wrote about this sleep-friendly supplement here.

Valerian and hops: the anti-stress, pro-sleep duo

These are two supplements often used together, and are well known for their sleep-improving abilities. Valerian and hops may help women in menopause by boosting levels of GABA, the calming neurotransmitter that stabilizes mood and boosts relaxation and sleep.

At least a dozen or more scientific studies have found valerian—used on its own or with hops—helps to improve sleep. Research shows that valerian can help people fall asleep more quickly, improve the quality of sleep, and increase amounts of nightly sleep. Valerian can also help ease the symptoms of insomnia. Studies specifically about women undergoing menopause show valerian is helpful to improving their sleep.

Research shows valerian can be effective in helping to reduce stress, lowering blood pressure and heart rate. Studies also show hops can be effective in reducing stress and anxiety.

A flavonoid in hops has also been found to help reduce weight gain, lower elevated cholesterol and reduce high blood sugar.

Want to know more about how valerian and hops affect sleep and health? Here you go.

CBD: the calming, sleep-promoting pain reliever
I am asked all the time: how does cannabis help sleep and health?

The cannabis plant is filled with hundreds of different compounds, and many have been studied for decades for their health benefits. The cannabis compounds that scientists have paid the most attention to are known as cannabinoids. Cannabinoids are now used in treatment for a broad—and growing—range of conditions and symptoms, from sleep and pain, to anxiety and inflammation, to Parkinson’s disease and cancer.

Cannabidiol—or CBD—is a cannabinoid that’s available in supplement form, and can help with stress and anxiety, pain, and sleep problems. Unlike medical cannabis, CBD is legal in all 50 states. Even if you live in a state where medical cannabis is currently not legal, you can still purchase and use CBD.

Let me be very clear: CBD is not “pot.” There is no “high” associated with CBD. (I’ll be writing more in-depth about the difference between CBD Instead, this compound has calming, anti-anxiety effects. CBD is a sleep promoter. Also of relevance for women in menopause, CBD works as an anti-oxidant and anti-inflammatory, as well as an analgesic—a pain reducer—in the body. (You can check out my full run-down on the science behind CBD here.)

CBD can reduce anxiety, making it effective in reducing sleep disruptions and improving sleep quality. CBD may improve insomnia, and increase overall sleep amounts. With its sleep-enhancing abilities combined with its power as an analgesic, CBD has been shown to reduce insomnia in people who suffer from chronic pain.

Cannabis has been used for centuries to treat nerves and anxiety, as well as other mood problems. CBD may help to improve both depression and anxiety, at least in part through its interactions with serotonin receptors in the brain. Research shows that CBD can reduce both mental and physical symptoms of anxiety.

Women who experience insomnia along with symptoms of anxiety or depression during menopause, as well as women who have aches and pains as a menopause symptom, may find relief from CBD.

Next, I’ll discuss other supplements that are used to treat menopause symptoms—and look at how they can affect sleep.

Sweet Dreams,

Michael J. Breus, PhD, DABSM
The Sleep Doctor™

Uses and side effects of black cohosh for menopause

Share on PinterestPeople with pre-existing conditions may have a higher risk of experiencing adverse side effects.

There is little to no long-term data on the risks associated with black cohosh use.

As black cohosh preparations are not regulated by the FDA, there is also a chance that products may contain other botanical or chemical ingredients that could cause harm.

Because of these uncertainties, the North American Menopause Society do not recommend the use of the herb for the treatment of menopause symptoms. Most health authorities and studies suggest that if black cohosh is used, it should only be taken for a maximum of one year.

Though rare, liver injury is the most studied, and potentially the most dangerous, complication associated with black cohosh use. Those with signs of jaundice or liver failure should immediately see a doctor. If the signs are severe, they should seek emergency care.

Common signs of jaundice include:

  • yellowing of the skin and eyes
  • severe upper stomach pain or cramps
  • nausea and vomiting
  • extreme tiredness not related to exercise or lack of sleep
  • dark urine

Many additional health complications of varying severity have been connected with the use of the black cohosh.

As the herb acts as a blood thinner, bleeding and blood pressure disturbances may occur with use. A doctor should assess symptoms that involve bleeding or become severe.

The full list of currently known side effects of black cohosh use includes:

  • abnormal or increased vaginal discharge
  • vaginal bleeding or stimulation of menstrual flow
  • abnormal heartbeat or altered blood pressure, typically lowered
  • blood clots, especially in the legs
  • breast cancer recurrence
  • fluid buildup
  • headache
  • irritability, moodiness, depression
  • breast pain or tenderness
  • chest discomfort
  • constipation
  • liver damage or failure
  • hepatitis infection
  • muscle weakness
  • minor skin irritations or lesions
  • eye inflammation
  • nausea and vomiting
  • dizziness or vertigo
  • overgrowth of the uterine lining
  • seizures
  • excessive sweating
  • general swelling
  • fatigue
  • mild visual impairments
  • weight gain

Certain people may be at a higher risk of complications if using black cohosh. Those on estrogen or hormone therapies may not be able to take it safely.

Factors that increase the likelihood of adverse reactions to black cohosh include:

  • hormone-sensitive conditions, such as breast and uterine cancers, and endometriosis
  • seizure disorders
  • liver disease
  • history of stroke
  • conditions involving blood clots
  • medication that lowers blood pressure
  • estrogen medications and hormone replacement therapies
  • blood-thinning and antiplatelet medications
  • nonsteroidal anti-inflammatory medications
  • alcohol use

In many classes of medications, there are ones that increase the risk of complications and interaction when used alongside black cohosh. These classes include:

  • liver medications
  • osteoporosis and arthritis medications
  • depression and mood medications
  • anti-seizure medications
  • antihistamines
  • cancer medications
  • cholesterol medications

Some people are allergic to black cohosh and its components. The herb may also contain small levels of salicylic acid, the active component in aspirin. People with aspirin intolerance or allergies should avoid it.

Black cohosh may also interact negatively with other herbs or traditional remedies. Supplements used to treat conditions, such as those considered risk factors for black cohosh use, might also raise the chance of side effects when used alongside this herb.

Natural supplements to avoid while using black cohosh include:

  • chaste-tree berries
  • evening primrose oil
  • blue cohosh
  • pennyroyal
  • ginkgo biloba
  • garlic
  • saw palmetto
  • willow bark
  • St. John’s wart

Dr. Brown is an assistant professor of pharmacy practice at Palm Beach Atlantic University, Lloyd L. Gregory School of Pharmacy, West Palm Beach, Florida.

Menopause occurs when the ovaries no longer produce estrogen, a process that begins in a woman’s mid-30s with almost complete cessation of estrogen production by her mid-50s. Menopause is defined as the cessation of menses for at least 12 consecutive months. Undergoing surgical procedures (eg, hysterectomies), chemotherapy, and irradiation can induce the immediate onset of menopause.

Though menopause is a normal part of the aging process for most women, this change can have physical and psychological implications. In fact, up to 85% of women experience menopausal symptoms, including hot flushes, night sweats, insomnia, and vaginal dryness that can lead to painful sexual intercourse.1 Additionally, concomitant depression and anxiety may stem from this biological process. Thus, it is not surprising that many women will seek medical advice for the alleviation of these symptoms as they can have a significant impact on their quality of life.

In addition to nonpharmacologic recommendations, such as smoking cessation, increased physical activity, and minimizing alcohol intake, hormone replacement therapy (HRT) is perhaps the most effective therapy for the relief of the aforementioned menopausal symptoms.1 In light of data that suggest a potential increased risk for cancer, cardiovascular disease, and venous thromboembolism (VTE), however, many women are hesitant to begin HRT.2-5

Many women prefer a more natural approach to treatment and are turning to the use of dietary supplements for the relief of menopausal symptoms. One small study showed that women who used dietary supplements as part of the management of menopause, either as monotherapy or in combination with HRT, reported overall control of their menopausal symptoms and an improved quality of life.6

Pharmacists are in the prime position to advise patients on the appropriate use of these supplements for symptom alleviation. Though many complementary alternative medicine options exist, some products that commonly are sought out by women to treat menopausal symptoms include black cohosh, soy, dong quai, ginseng, vitamin E, red clover, and kava. This article focuses on the use of black cohosh and soy.

Black Cohosh (Actaea racemosa)

Studies suggest that black cohosh appears to reduce menopausal symptoms modestly, especially hot flushes.7,8 One 3-month study found that 40 mg/day of black cohosh was similar in hot flush reduction, compared with transdermal estradiol 25 mcg applied weekly. Effects were seen by the first month and maintained throughout the remainder of the study.8

Additionally, the use of black cohosh in combination with St. John’s wort has shown improvements in both hot flush complaints and depressive symptoms.9 Although most studies have only assessed the safety and efficacy of black cohosh for up to 6 months, 2 studies demonstrated the safe use of black cohosh supplements for up to 1 year.10,11

Black cohosh appears to be effective in the treatment of menopausal symptoms by acting like an estrogen receptor modulator, producing estrogenic effects on bone, but causing antiestrogenic effects on other tissues. One animal study suggests that black cohosh does not increase the risk for breast cancer; however, it increased the risk for metastatic cancer in those animals with existing cancer.12

Conflicting data exist on whether black cohosh is safe and effective for the alleviation of hot flushes in women who are breast cancer survivors.13-15 Though black cohosh does not appear to affect estrogen receptors, the use of the supplement has not been studied in long-term trials, and therefore, the use of black cohosh?containing products is not recommended in women with hormone-sensitive cancers, such as breast, uterine, and ovarian.

Common adverse effects reported with black cohosh are gastrointestinal (GI) upset, abdominal pain, breast tenderness, and vaginal spotting or bleeding. 16-18 A rare but serious potential adverse effect is hepatitis. Thus, routine assessment of liver function is advised.19 It is also important to note that black cohosh should not be confused with blue or white cohosh.

Research suggests that black cohosh modestly inhibits the cytochrome P450 isoenzyme 2D6.20 Drugs such as amitriptyline, haloperidol, paroxetine, and ondansetron, among others, are metabolized through this isoenzyme, and concentrations may be prolonged with concomitant administration of black cohosh. Caution is warranted with concomitant use of these agents.

Women electing to use black cohosh also should be counseled that immediate relief of symptoms should not be expected, and it can take up to 4 weeks to see effects.8


The effects of soy on relieving hot flushes have been investigated after recognizing that Asian women who typically have a diet high in soy reported lower rates of hot flushes, compared with American women. Soy contains isoflavones, a type of phytoestrogen that possesses weak estrogenic activity to relieve hot flushes.1 Clinical data show conflicting results on the efficacy of soy to minimize menopausal symptoms, however.11,21-24 One 6-month trial comparing 0.625 mg daily of conjugated equine estrogens with a standardized isoflavone-containing product demonstrated similar efficacy between the 2 products.25

The average dose of isoflavones studied has ranged from 40 to 80 mg daily. Though many foods such as soy milk, soy sauce, and soy nuts contain isoflavones, supplementation is typically required to achieve maximum benefits.1 This is because approximately 1 g of soy only contains between 1.2 and 1.7 mg of isoflavones, which is much less than the studied amounts of 40 to 80 mg daily.

The most common adverse effect is GI distress, including diarrhea, nausea, bloating, and constipation.26 Due to estrogenic effects, concern exists about soy’s potential to increase the risk for breast and endometrial cancers. This concern is validated as findings from a 5-year study of isoflavones suggest a potential risk for endometrial cancer.27 Therefore, similar to black cohosh, the use of soy in patients with a history of hormone-sensitive cancers is not recommended.1

Patients may ask if the use of soy increases the risk for VTE, especially in light of the risk associated with estrogen therapy. Currently data do not suggest that soy has any effects on coagulation or fibrinolysis.28

Drug interactions are also an important consideration when counseling patients on these products. Normal gut flora is partially responsible for converting isoflavones to more biologically active components. Thus, antibiotics that wipe out gut flora reduce the efficacy of soy-containing products, decreasing the efficacy of soy during this time and following completion of the antibiotic until regeneration of gut flora occurs.29 Additionally, information from a case report of a patient receiving warfarin and consuming soy milk found the international normalized ratio was reduced.30 Thus, close monitoring of patients on warfarin using soy supplements is warranted, especially with initiation and titrations.

Role of the Pharmacist

Dietary supplements commonly are sought out by patients for various reasons. As they are available over the counter, patients may believe the use of herbal products is undoubtedly safe. As a pharmacist, it is prudent to assess each patient’s symptoms, ask about medical conditions and current medications, as well as consider a patient’s allergy information, prior to making a recommendation.

Neither black cohosh nor soy should be recommended in women with a history of hormone-sensitive cancers. Additionally, both agents have potential drug?drug interactions that will likely merit close monitoring. Thus, basic knowledge about common herbals, such as black cohosh and soy, that are used for the management of menopausal symptoms is imperative to optimizing patient outcomes.

  1. AACE Menopause Guidelines Revision Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of menopause. Endocr Pract. 2006;12(3):315-337.
  2. Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004(13);292:1573-1580.
  3. Manson JE, Hsia J, Johnson KC, et al. Estrogen plus progestin and risk of coronary heart disease. N Engl J Med. 2003;349(6):523-534.
  4. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen and progestin on breast cancer and mammography in healthy post-menopausal women: The Women?s Health Initiative randomized trial. JAMA. 2003;289(24):3243-3253.
  5. Barnabei WM, Grady D, Stovall DW, et al. Menopausal symptoms in older women and the effects of treatment with hormone therapy. Obstet Gynecol. 2002;100(6):1209-1218.
  6. Kam IW, Dennehy CE, Tsourounis C. Dietary supplement use among menopausal women attending a San Francisco health conference. Menopause. 2002;9(1):72-78.
  7. Osmers R, Friede M, Liske E, et al. Efficacy and safety of isopropanolic black cohosh extract for climacteric symptoms. Obstet Gynecol. 2005;105(5 Pt 1)1074-1083.
  8. Nappi RE, Malavasi B, Brundu B, Facchinetti F. Efficacy of Cimicifuga racemosa on climacteric complaints: a randomized study versus low-dose transdermal estradiol. Gynecol Endocrinol. 2005;20(1):30-35.
  9. Uebelhack R, Blohmer JU, Graubaum HJ, et al. Black cohosh and St. John’s wort for climacteric complaints: a randomized trial. Obstet Gynecol. 2006;107(2 Pt 1):247-255.
  10. Raus K, Brucker C, Gorkow C, Wuttke W. 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.
  11. Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, mulitbotanicals, soy, hormone therapy, or placebo. Ann Intern Med. 2006;145(12)869-879.
  12. Seidlova-Wuttke D, Hesse O, Jarry H, et al. Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimicifuga racemosa) extract: comparison with estradiol-17beta. Eur J Endocrinol. 2003;149(4):351-362.
  13. Davis VL, Jayo MJ, Hardy ML, et al. Effects of black cohosh on mammary tumor development and progression in MMTV-neu transgenic mice. Presented at: Annual Meeting of the American Association for Cancer Research; July 11-14, 2003; Washington, DC. Abstract R910.
  14. 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.
  15. Hernandez Munoz G, Pluchino S. Cimicifuga racemosa for the treatment of hot flushes in women surviving breast cancer. Maturitas. 2003;44(suppl 1):S59-S65.
  16. 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.
  17. Bai W, Henneicke-von Zepelin HH, Wang S, et al. Efficacy and tolerability of a medicinal product containing an isopropanolic black cohosh extract in Chinese women with menopausal symptoms: a randomized, double blind, parallel-controlled study versus tibolone. Maturitas. 2007;58(1):31-41.
  18. Pepping J. Black cohosh: Cimicifuga racemosa. Am J Health Syst Pharm. 1999;56(14):1400-1402.
  19. Whiting PW, Clouston A, Kerlin P. Black cohosh and other herbal remedies associated with acute hepatitis. Med J Aust. 2002;177(8):440-443.
  20. Gurley BJ, Gardner SF, Hubbard MA, et al. In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther. 2005;77(5):415-426.
  21. Han KK, Soares JM Jr, Haider MA, de Lima GR, Baracat EC. Benefits of soy isofalvone therapeutic regimen on menopausal symptoms. Obstet Gynecol. 2002;99(3):389-394.
  22. Quella SK, Loprinzi CL, Barton DL, et al. Evaluation of soy phytoestogens for the treatment of hot flashes in breast cancer survivors: A North Central Cancer Treatment Group Trial. J Clin Oncol. 2000;18(5):1068-1074.
  23. Van Patten CL, Olivotto IA, Chambers GK, et al. Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomized controlled clinical trial. J Clin Oncol. 2002;20(6):1449-1455.
  24. Huntley AL, Ernst E. Soy for the treatment of perimenopausal symptoms–a systematic review. Maturitas. 2004;47(1):1-9.
  25. Kaari C, Haidar MA, Junior JMS, et al. Randomized clinical trial comparing conjugated equine estrogens and isoflavones in postmenopausal women: a pilot study. Maturitas. 2006;53(1):49-58.
  26. Albertazzi P, Pansini F, Bonaccorsi G, et al. The effect of dietary soy supplementation on hot flushes. Obstet Gynecol. 1998;91(1):6-11.
  27. Unfer V, Casini ML, Costabile L, et al. Endometrial effects of long-term treatment with phytoestrogens: a randomized, double-blind, placebo-controlled study. Fertil Steril. 2004;82(1):145-148.
  28. Teede HF, Dalais FS, Kotsopoulos D, et al. Dietary soy containing phytoestrogens does not activate the hemostatic system in postmenopausal women. J Clin Endocrinol Metab. 2005;90(4):1936-1941.
  29. Morito K, Hirose T, Kinjo J, et al. Interaction of phytoestrogens with estrogen receptors alpha and beta. Biol Pharm Bull. 2001;24(2):351-356.
  30. Cambria-Kiely JA. Effect of soy milk on warfarin efficacy. Ann Pharmacother. 2002;36(12):1893-1896.

Black Cohosh Hepatic Safety: Follow-Up of 107 Patients Consuming a Special Cimicifuga racemosa rhizome Herbal Extract and Review of Literature


European Medicines Agency (EMEA) and the Committee on Herbal Medicinal Products (HMPC) on July 2006 have released an alert to get European sanitary authorities aware of 42 cases of suspected hepatotoxic reactions in patients consuming Cimicifuga racemosa rhizome. In the public statement EMEA itself considered reliable as hepatotoxic reactions only four cases, on the base of RUCAM score: two were considered possible and two probable. Lacking in almost all of them a precise description of cases, especially a botanical-chemical analysis of the suspected substance, we think there is no real proof of supposed C. racemosa rhizome hepatotoxicity. In our department we administer from about 10 years C. racemosa as special herbal dry extract as single substance or mixed with other medicinal plants at the dose of 500–1000 mg daily, for treatment of menopause related disorders without any reported adverse effect. After EMEA’s official signal we have contacted all our patients using a C. racemosa rhizome herbal extract continuously from more than 12 months to verify possible hepatotoxic effects. We followed-up 107 women, and asked them by telephone (33/107) and/or after anamnesis and clinical examination (74/107) to undergo a blood sample examination. In all the patients there was no sign of hepatic disease, or worsening of already altered but stable parameters. We think on the base of these data and current literature C. racemosa rhizome extract should not be considered a potential hepatotoxic substance.

1. Introduction

Currently hormone replacement therapy (HRT) is commonly used to reverse symptoms and diseases associated with falling oestrogen and progesterone levels. However HRT is associated with adverse effects and an increased risk of breast cancer . Many women therefore take a dislike to HRT and choose to employ herbal remedies for menopausal symptoms, one of most used worldwide is Black Cohosh.

Cimicifuga racemosa Nuttal (syn. Actaea racemosa L) common name Black Cohosh (Ranunculaceae; Figure 1), is an herbaceous perennial plant of North America. It is a coarse, perennial, woodland herb with large compounds leaves, and a thick, knotted, rhizome system . Traditionally it was used by Native Americans (Penobscot, Winnebago and Dakota) for the treatment of coughs, colds, constipation, fatigue and rheumatism and to stimulate lactation. Since 1832 a hydroalcoholic extract was described as treatment for pain and inflammation in endometriosis and dysmenorrhea ; and a fluid extract was listed in the US National Formulary from 1840 until 1946 ; and was a major constituent of the once popular patent medicine “Lydia Pinkham’s Vegetable Compound” used for treatment of “painful complaints and weakness” in females. Actually, C. racemosa is widely employed in various pharmaceutical–industrial preparations often mixed with other medicinal plants to alleviate menopausal and post-menopausal symptoms, including hot flushes, profuse sweating, sleep disturbances, anxiety and depression.

Figure 1
Cimicifuga racemosa Nuttal.

Safety data from post-marketing surveillance study have generally found very few serious adverse events, nevertheless the lack of placebo or positive control arms in main studies, the lack of serious adverse events suggests that C. racemosa has a very good safety profile as confirmed in a review of more than 3800 climateric women .

Recently the European Medicines Agency (EMEA) and the Committee on Herbal Medicinal Products (HMPC) on July 2006 have released a public statement , although lacking of many data on patients and herbal extracts, to get European sanitary authorities aware of 42 (34 directly reported from European national competent authorities and 8 published) cases of suspected hepatotoxic reactions in patients, probably all women and for treatment of menopause related disorders, consuming C. racemosa often mixed with other medicinal plants. Following the review of available data, the statement considered real a potential connection between herbal medicinal products containing C. racemosa and human hepatotoxic reaction. Nevertheless this highly authoritative review of such a number of cases, in the summary EMEA states that “overall, all discussed cases of literature and pharmacovigilance reports are poorly documented. In many cases there is not even information about the time frame of treatment with Cimicifuga containing products or about the relation to the onset of reaction available. Therefore, they are insufficiently documented according to RUCAM score. The Non-EU cases are not validated by a health care professional but reported by patients” . Because C. racemosa extracts are sold as OTC integrators, Italian sanitary authorities decided a precautionary withdrawal from the national market, that later has been reversed, and stringent label warnings have been introduced for C. racemosa extracts in United Kingdom. So actually there are some concerns about C. racemosa extracts safety especially in patients suffering of liver disease.

2. Methods

2.1. Participants

In our department we administer C. racemosa rhizome extract regularly for treatment of menopause related complaints, from about 10 years to 798 patients as only substance or mixed with other medicinal plants like Glycine max isoflavones, Trifolium pratense and. Medicago sativa, at the dose of 500 or 1000 mg daily as dry extract, standardized and titrated in 2.5% of actein, a triterpene glyocoside (Figure 2), for treatment of menopause related disorders like anxiety, depression, flashes and myalgia. We regularly exclude from the treatment patients affected by cancer of sexual organs: breast, ovaries, uterus and hypophysis, unless already treated with conventional therapy from more than 7 years and considered recovered. In our experience we had no report of adverse reaction to C. racemosa extracts, both as single prescription either mixed with other medicinal plants extracts, but minor complaints.

Figure 2
The main constituents of Black Cohosh.

After EMEA’s official statement indicating a possible risk of hepatotoxicity in patients assuming extract of C. racemosa, we have contacted all our available patients consuming the extract continuously from at least 12 months.

So we considered 158 patients eligible, for control of a possible hepatotoxic adverse reaction to C. racemosa herbal extract to whom it was prescribed following our patterns. Of our contact list 107 climateric women were followed-up by telephone or direct clinical examination in our department.

2.2. Study Protocol

Baseline characteristics of study participants are available in Table 1. They were an heterogeneous group of patients in different phases of menopause and most of them asked a complementary treatment for menopause related anxiety and depression because of unsatisfied or fear of synthetic drugs. Most of them were in good health, but complaints referred to menopause. Only five patients were suffering of chronic hepatobiliary disease (four patients suffering of benign hepatic disease and one chronic toxic hepatitis). We excluded from follow-up patients who had suspended the treatment for more than 15 days, also non-consecutive, or had spontaneously reduced the dose prescribed.

Table 1 Baseline characteristics of study participants.

We followed-up 107 women asking them by telephone (33/107) and/or after clinical examination (74/107), to undergo a blood sample examination to control main laboratory parameters to evaluate liver function.

As shown in Table 2 patients underwent a blood sample examination to evaluate: total leukocyte count, hepatic transaminases, γ-glutamiltranspeptidase, alkaline phospahatase, albumin, coagulation and total bilirubin. By telephone the patients were questioned if they were still regularly consuming the herbal extract and they were asked some question on the base of the same check-list used during clinical examination in hospital.

Table 2 Follow up of patients assuming Cimicifuga.

3. Results

In all the patients (comprehending four patients suffering of benign hepatic disease and one suffering of chronic toxic hepatitis) there were no sign of hepatic disease neither alteration of plasma hepatic parameters, or worsening of already altered but stable parameters. Only nine patients were suffering of minor transient complaints (see Figure 2) and after 1 month underwent by telephone a new follow-up with a blood sample control that was negative for any disease.

To our patients we administered very high doses respect to median dose used in clinical trials (median range 40–80 mg daily) , but after 12 months of regular use there were no laboratory data, neither clinical signs, referring to a possible hepatic adverse reaction.

Few patients (9/107) were suffering of minor complaints, like fatigue, aspecific abdominal pain and paresthesias, (Table 2), controlled again after 1 month did not show any sign of liver disease.

4. Discussion

4.1. Hepatotoxic Drug Reactions

Between 0.1 and 3% of all hospital admissions are related to drug toxicity, but it is suspected that many cases are not recognized. Since liver is central to the metabolic disposition of virtually all drugs, drug-induced hepatic injury is a potential complication of nearly every medication. Fortunately adverse hepatic drug reactions are relatively uncommon in comparison with the number of drug prescriptions. In majority of the cases, hepatic drug reactions present as acute hepatitis, which is usually reversible and relatively benign; however, the spectrum of liver disease may range from mild biochemical abnormalities to acute hepatic failure.

When a drug is found to cause even rare hepatotoxicity but is used by millions, it may disproportionally be removed from the market, although this substance is a real danger only for few patients. And should be stressed that to incriminate any drug in an episode of liver dysfunction is a difficult step-by-step process that requires: high degree of suspicion, compatible chronology, awareness of its hepatotoxic potential, competent exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology .

It is very important in the step-by-step process to rule out other causes of liver injury including hepatic infections, alcoholic and autoimmune hepatitis, biliary tract disorders and hemodynamic based diseases . Finally genetic and metabolic disorders may produce liver injury such as hemochromatosis and Wilson’s disease. Liver injury in the absence of other known causes may be drug-related and requires additional information, such as that obtained through a careful drug history, in relation to the onset of injury .

In respect to the hepatotoxic potential of screened drugs, their potential for causing liver damage is not the same, and almost all marketed medications have been incriminated in incidences of hepatotoxicity ; probably because the most important factor for hepatotoxicity is genetic variability . Genetic polymorphisms have a strong influence on drug metabolism and may increase the risk of hepatotoxicity .

The main causative group of drugs, in a large cohort of hepatotoxicity cases collected in the Spanish registry, were antibiotics followed by non-steroidal anti-inflammatory drugs ; and statins have been shown to cause elevations of aminotrasferase levels and severe liver injury in animals; while in humans such elevations are common but rarely if ever, lead to clinically significant hepatotoxicity . All drugs that are well known hepatotoxic, and well stable in the market, thanks to their therapeutic advantages, as such as paracetamol, one of main causes worldwide of liver transplant, nevertheless sold over-the-counter in many Western countries.

4.2. Safety of Black Cohosh in Experimental Trials

A study in vitro on HepG2 cells and in vivo on rats to evaluate potential hepatotoxicity of C. racemosa; showed cytotoxic reactions in vivo at concentrations of 75 μg ml−1; and significant initial mithocondrial swelling in rats fed with 100 and 300 mg kg−1 daily of C. racemosa extract, while clear microvesicular steatosis of the hepatocytes and fragmentation of the rough endoplasmic reticulum at 1000 mg kg−1 daily . The Authors conclude that toxicity is not clinically relevant for most patients but may become important in patients with underlying risk factors , as like as for any drug; moreover a dose of 100 mg kg−1 is very high and corresponds in a woman of 50 kg at 5 g of extract daily.

Natural and synthetic estrogens are known to alter hepatobiliary physiology, and certain genetically susceptible women become icteric during pregnancy, when high serum oestrogen levels are present. Although not all the mechanisms responsible for hepatic injury produced by estrogens are known, it is consistently reported that Black Cohosh extracts and isolated compounds do not posses estrogenic activity, regardless of source, extraction procedure, dose or length of exposure .

Chronic toxicity was not observed in rats at a dose of 500 mg kg−1 per day for 27 weeks or in dogs at 400 mg kg−1 per day for 26 weeks . Furthermore, a 40% 2-propanol extract of Black Cohosh was negative in the Ames test . In mice, the LD50 of a Black Cohosh extract was 7.7 g kg−1 for intragastric administration and 1.1 g kg−1 for intravenous administration .

4.3. Safety of Black Cohosh in Humans

In clinical trials only minor adverse side effects have been reported, including nausea, vomiting, head-aches and dizziness: a review of eight clinical trials concluded that extracts of the rhizome of C. racemosa might be a safe alternative for women seeking alternative estrogen replacement therapy .

Black Cohosh also contains several catechols, such as caffeic acid, piscidic acid and fukiic acid esters that exhibit some antioxidant properties, including fukinolic acid, cimicifugic acid A and cimicifugic acid B . Such catechols could be of significant concern in toxicology because of the possibility that they could be activated, either metabolically or chemically, to electrophilic quinones. The potential of such quinones to cause toxicity and carcinogenesis is well documented, and can occur via arylation of cellular proteins and DNA or redox cycling leading to the formation of reactive oxygen species such as the hydroxyl radical . Nevertheless has been shown in six perimenopausal women after administration of a single dose of either 32, 64 or 128 mg of C. racemosa that no corresponding mercapturic acids were found in the urine . In a previous study, potential toxicity was suspected because catechols from Black Cohosh are activated to quinoid metabolites, but catechols are not absorbed across the bowel .

In a recent trial on 351 randomized women, placebo controlled, Black Cohosh both used as single substance and mixed in multi herbs remedies after 12 month of treatment, did not show any effect on lipids, glucose, insulin and fibrinogen .

Instead an important issue about safety is probably the interaction with synthetic drugs because of the interference with the metabolic pathway of cytochrome P4503A4 , a potential cause of important adverse reactions, especially in patients assuming multi drug regimen therapies as confirmed by a recent work in which ethanol and isopropanol extract induced inhibition of CYP1A2, 2C9, 2D6, 3A4.

To be added a case of cutaneous pseudolymphoma in a patient assuming a commercial extract of C. racemosa has been reported recently ; and a case of muscle damage with asthenia, high levels of creatine phosphokinase and lactate dehydrogenase following assumption of a dietary supplement derived from C. racemosa has also been reported .

4.4. The EMEA and HMPC Signal of Hepatic Toxicity

The EMEA and the HMPC have been made aware of a number of case reports of hepatotoxicity (liver injuries) in patients using C. racemosa rhizome. Following review of all available data, the HMPC considered that there is a potential connection between herbal medicinal products containing C. racemosa rhizome and hepatotoxicity on the base of 42 case reports of hepatotoxicity, collected from European National Competent Authorities (34 cases) as well as literature case reports (8 cases). Of these, only 16 cases were considered sufficiently documented to allow the Committee to assess if use of C. racemosa rhizome could be linked to the liver injuries. As a result of the assessment, five cases were excluded and seven cases were considered unlikely to be related. In the remaining only four cases (two autoimmune hepatitis, one hepatocellular liver injury and one fulminant hepatic failure), there was a temporal association.

So there are very few cases well documented and few data available, for a concrete decision about its suspected hepatotoxicity; and in many reports C. racemosa extracts were mixed with many other substances so that was impossible to get any reliable reference to the assumption of C. racemosa.

Besides, in the best four cases is not possible to evidence a clear hepatotoxic relationship with the consumption of C. racemosa extract: (a)In case 28, as numbered in the EMEA statement, (RUCAM Score 4) the only collected from European national competent authorities, the adverse reaction is considered possible but information on differential diagnostic assessment were not available. The patient was assuming 80 mg of an unknown type of extract daily, for an unknown period and without differential diagnostic available.(b)In this published case report (RUCAM score 3) the patient was a 54-year-old woman suffering of hypothyroidism, fibromyalgia, osteoarthritis and depression that had taken 1000 mg of Black Cohosh (no description of extract or crude drug) daily for several months. The patient was on fluoxetine, propoxyphene and paracetamol (a well known hepatotoxic substance) concomitantly and drinking two glasses of wine in the evening. In the statement it is written “that since there is no further information on the herbal preparation, the case report is not of great relevance in the assessment of cimicifuga-related hepatotoxicity” .(c)A 57-year-old multimorbid African American woman (RUCAM Score 7) with a history of polymyositis had developed an autoimmune hepatitis about 3 weeks after the first intake of C. racemosae rhizoma (brand and dose unknown; no information if it was a combination product). After cessation of the drug and starting a therapy with steroids and azathioprine, the patient recovered. The autoimmune hepatitis could have been as well a manifestation of a multisystem autoimmune disease. According to the draft recommendations of the Scientific Advisory Panel Subgroups on Hepatotoxicity, the case could be classified as idiosyncratic liver necrosis.

The causal relationship to Black Cohosh in the present case was first assessed as “unclassifiable” as information provided concerning the reaction was regarded as incomplete and contradictory, while the follow-up publication includes more (although to some extent contradictory) therapy information.

(a)This a well-documented case (RUCAM Score 6) . The admitted amount was 500 mg drug per day. The reaction was described as hepatocellular, other causes for acute hepatitis were excluded. The provisional clinical diagnosis was autoimmune hepatitis. Therapy was started with 60 mg prednisone/day for 5 weeks. Liver enzymes improved, but due to worsening coagulopathy and encephalopathy the patient underwent an orthotopic liver transplantation. In the explanted organ, histologically features of acute hepatitis, fibrous linkage of portal tracts and cholestasis were seen after 5 weeks on corticosteroids. Nevertheless in this case too, the exact content of the remedy based on Black Cohosh is not known: was it an extract or crude drug? Did it contain other toxic substances? Heavy metals? Later on nevertheless Levitsky et al. reported that the patient did not drink, use drugs or take any other medication; but in a US District Court proceeding the woman testified that she regularly drank wine, and used both prescribed and non-prescribed pharmaceuticals .

4.5. The Problematics of Herb ADRs

We would like to remark that it is very important before an official statement about any adverse reaction referred to an herb based product to know the brand, dose of substance assumed, type of extract, content of possible contaminants (wrong plants, pesticides, heavy metals and aflatoxins) . When needed to establish a connection between herb consumption and an adverse reaction, especially if liver related, the same rules of conventional drugs can be followed only if the case report deal with a single substance of a medicinal plant; while if it is a multiherb preparation a direct toxic connection with only one herb cannot be correctly established, unless it is a well known hepatotoxic substance for example, Teucrium chamaedrys; or it is contained in a very high ratio respect to other herbs. To date in our opinion paradoxically the EMEA statement could be regarded as the proof the risk of Black Cohosh hepatotoxicity is scarce, because actually there is not any full proved case of hepatotoxicity reported in front of millions of doses used yearly in the world (about 1 500 000 women are using C. racemosae extracts only in Europe) ; and its safety was already been sufficiently established by the fact that in over 3800 participants in clinical trials there were no hepatotoxic reactions reported .

In our series of patients assuming daily a very high dose of extract (much more than 40–80 mg used in most clinical trials and usually recommended) for at least 12 months we did not find any clinical or laboratory proof of liver disease; but the five already suffering of chronic liver disease, that maintained stable clinical and laboratory parameters (Table 3).

Patients at baseline and control 1 Baseline 1 Control 2 Baseline 2 Control 3 Baseline 3 Control 4 Baseline 4 Control 5 Baseline 5 Control
Leukocyte 5780 mm3 6300 mm3 3990 mm3 4100 mm3 6700 mm3 6900 mm3 8000 mm3 7450 mm3 3450 mm3 4500 mm3
Tot bilirubin 1.4 mg dl−1 1.3 mg dl−1 0.9 mg dl−1 0.9 mg dl−1 0.7 mg dl−1 0.6 mg dl−1 0.2 mg dl−1 0.3 mg dl−1 0.4 mg dl−1 0.5 mg dl−1
AST 57 IU l−1 67 IU l−1 38 IU l−1 39 IU l−1 45 IU l−1 46 IU l−1 38 IU l−1 42 IU l−1 41 IU l−1 33 IU l−1
ALT 47 IU l−1 52 IU l−1 36 IU l−1 33 IU l−1 37 IU l−1 35 IU l−1 20 IU l−1 18 IU l−1 45 IU l−1 42 IU l−1
Alkaline phosphatase 150 U l−1 156 U l−1 119 U l−1 118 U l−1 110 U l−1 105 U l−1 120 U l−1 122 U l−1 110 U l−1 80 U l−1
γGT 55 U l−1 59 U l−1 22 U l−1 25 U l−1 35 U l−1 32 U l−1 45 U l−1 44 U l−1 48 U l−1 35 U l−1
Albumin 3.5 g dl−1 3.6 g dl−1 4.1 g dl−1 4.2 g dl−1 3 g dl−1 2.9 g dl−1 3.8 g dl−1 4 g dl−1 4.2 g dl−1 4.4 g dl−1
INR 0.8 0.9 1.2 1.3 0.9 0.9 1.1 1.1 1 1.2

Table 3 Follow up of five patients suffering from stable chronic liver disease.

In our series we had a relative low number of patients (32/107) assuming contemporary synthetic drugs to exclude reliably an interference on hepatic metabolism, although they did not report any significant side effect.

5. Conclusions

A reporting rate higher than the background rate is taken as a “signal” of a possible causal relationship between the drug and the event , but in the EMEA statement the reported cases are so faintly circumstantiated that we think there is no evidence for an official signal. On the base of our data (although a small series of patients, but assuming high doses of C. racemosae extracts) and current literature, we think C. racemosa rhizome herbal extract should be considered safe concerning liver toxicity.

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