When deciding whether to use a botanical supplement, consumers may consider whether it is safe and whether it is effective. Those who read the disclaimer printed on every package will learn that claims of safety and efficacy have not been evaluated by the U.S. Food and Drug Administration. That is because federal law does not require such tests for botanicals before they hit the market.
It may not be surprising, then, that some 80 botanical substances have been nominated for study by the National Toxicology Program (NTP). Black cohosh extract (BCE), marketed to women for menstrual and menopausal symptoms, is one such substance.
The NTP approach to testing black cohosh offers a glimpse of challenges and processes involved in evaluating botanical substances. NTP genetic toxicologist Stephanie Smith-Roe, Ph.D., described BCE testing April 7 at the Duke University Integrated Toxicology and Environmental Health Seminar Series.
Plants and products vary
Plants used in botanical supplements experience a variety of growing conditions and methods of harvesting, storage, and processing. When it comes to testing for effects on health, variations like those listed below can influence both test design and outcomes, Smith-Roe explained.
- The specific species and plant part used.
- Adulteration with other plants or pharmaceuticals.
- Contamination, such as with metals or mold.
- Variation in methods used to produce extracts, tinctures, and teas.
- Numerous constituents, including unknown compounds, not all of which are active.
- Potential interactions between constituents.
To study BCE, scientists first examined several products on the market and looked for constituents known to be present in cohosh extracts, as well as other compounds. Smith-Roe noted that more than 100 compounds have been found in BCEs.
The high number of compounds is not unusual in botanicals, explained Cynthia Rider, Ph.D., an NTP toxicologist who planned the 2016 NTP workshop on botanicals. “Identifying the active constituents of botanicals was one of the key topics at that workshop,” Rider said.
After short-term and 90-day studies on a representative sample, researchers did not find significant toxicities, nor did they find the estrogenic activity they expected, given the reasons women take black cohosh. Smith-Roe pointed out that this finding is consistent with published studies.
BCE contains salicylic acid — the active metabolite of aspirin. Other compounds in BCE act on the neurotransmitters dopamine and serotonin, which might affect mood. “That could explain why some consumers feel that they benefit from taking this botanical,” Smith-Roe suggested.
Evaluate for DNA damage
The next step involved tests for genotoxicity, like all materials tested at NTP. Genotoxicity refers to cellular DNA damage that may lead to cancer or birth defects.
Scientists found biomarkers of damage to chromosomes in red blood cells. “Genotoxicity is a safety concern,” said Smith-Roe. Because of the differences in chemical composition among products, would other cohosh extracts show similar activity?
They did. The results, which are being prepared for submission to a peer-reviewed journal, showed positive dose-response genotoxic activity in an assay that used a human cell line.
Next — compounds and mechanisms
Another finding was that animals exposed to BCE developed a form of anemia called nonregenerative macrocytic anemia. The characteristics of this anemia suggested it might be caused by disrupting the metabolism of folate.
Chromosomal damage, of the kind observed in the genotoxicity tests, can also be caused by disrupting folate metabolism. Considering that BCE is marketed to women of childbearing age, and that low folic acid is associated with birth defects, NTP has undertaken studies to clarify whether BCE affects how cells use either folate or vitamin B12. Both vitamins are crucial for this pathway to operate normally.
What about people?
Meanwhile, as scientists unravel which components cause the effects, and how, NIEHS clinical researchers are studying whether women currently taking BCE are showing any changes in blood and other health indicators.
Kristine Witt, from NTP, is overseeing the clinical study. “We were intrigued by the results we found in animal genotoxicity studies and concerned that similar effects might be seen in women who were regular users of this botanical product,” she said. Women interested in enrolling in the study can find details on the NIEHS Black Cohosh Study webpage.
Mercado-Feliciano M, Cora MC, Witt KL, Granville CA, Hejtmancik MR, Fomby L, Knostman KA, Ryan MJ, Newbold R, Smith C, Foster PM, Vallant MK, Stout MD. 2012. An ethanolic extract of black cohosh causes hematological changes but not estrogenic effects in female rodents. Toxicol Appl Pharmacol 263(2):38−47.