Opening the annual meeting of the Botanical Safety Consortium (BSC) on Monday, Hellen Oketch-Rabah, deputy director of the Food and Drug Administration’s Office of Dietary Supplement Programs (ODSP) and member of the BSC Steering Committee, underscored the urgent need to develop robust safety tools for botanical compounds that are intended for human consumption.
“Dietary fruits and vegetables are as old as man and as old as time,” she said. “However, with the continuing rise in popularity of botanicals, the astute in the area of specialization will recognize that our ancestors had to learn that plants are highly diverse and creative.”
Among the examples of creative plants harnessed by modern mankind, she highlighted coffee cherries for powering most of North America with caffeine, Pacific Yew and Mexican periwinkle for anti-cancer drugs, the wooly foxglove for the treatment of heart failure and irregular heartbeat and the opium poppy for supplying the most powerful natural painkiller.
A public-private partnership for botanical safety
Founded in 2019, the Botanical Safety Consortium was established as a public-private partnership bringing together scientists from government, academia, industry and nonprofit organizations to develop better tools for identifying and assessing potential risks from botanicals as complex mixtures.
The complexity of determining safety
According to Oketch-Rabah, the chemistry of botanical plants presents a significant challenge for researchers and manufacturers when considering botanical safety because a single plant can contain between 100 and 1,000 different molecules. These compounds include primary metabolites essential to plant survival and secondary metabolites, which can contribute to both therapeutic effects and potential toxicity.
“Think about a factory where there are ingredients, in-process products and finished products, and all the equipment being used as well as personnel,” she said. “That is what I view plants as, the most creative synthetic factories.”
It is also still not fully understood how the compounds interact within plants, and the distinction between primary and secondary metabolites is likewise not always clear. Unlike single-molecule drugs, botanical products can vary significantly in chemical composition, even when made from the same plant species. Factors including plant variety, climate, geographic location, cultivation technique and processing can alter the final extract, making standardized production critical to achieving consistent results.
“With all these factors affecting what you get in your final extraction, there is an inherent variability that presents a major challenge for ensuring the product consistency and safety, hence the complexity in determining safety as well, [and] against all this backdrop and background, the use of botanicals is widespread and growing,” Oketch-Rabah said.
According to the American Botanical Council’s 2024 Herb Market Report, U.S. retail sales of herbal dietary supplements reached a record $13.2 billion in 2024, reflecting a 5.4% increase from the previous year.
Oketch-Rabah also noted that the global demand for plant-based ingredients is reshaping the personal care industry and that international health bodies like the World Health Organization (WHO) are highlighting the role of traditional and complementary medicine, which relies heavily on botanicals.
“Another thing to consider is that the dose or intake level of botanicals tend to be much higher compared to medicines,” she added. “With medicines when you’re given a dose, it’s usually maybe between two milligrams to maybe 600 milligrams per day on the high end, whereas with botanicals, you find that the intake levels range between 10 milligrams to a thousand milligrams per day, or even 6,000 or more milligrams per day.”
It is in response to these doses, increasing number of marketing claims and the expanding use of botanicals that the BSC recognizes the urgent need for tools to protect against rare but potential adverse effects, particularly since botanicals are often incorporate in multi-ingredient formulations.
A two-pronged approach
As part of its strategy, BSC identifies priority toxicity endpoints and then selects botanical candidates and appropriate assays for each endpoint. Through chemical analysis and evaluation, the consortium then builds a library of botanicals and a corresponding toolbox of assays. The results are analyzed to develop a comprehensive framework and toolbox that will be applied for each endpoint.
‘Adverse effects do occur’
While regulators continue to track the rare adverse effects of botanicals across the globe, no case has been quite as prominent in drawing attention to the challenges of assessing botanical safety as the controversy surrounding ephedra in the 1990s and early 2000s.
After reports linked ephedrine-containing supplements to serious cardiovascular and neurological adverse events, the FDA banned their sale in 2004.
“This followed numerous adverse events, some of which were very severe, many of which actually even led to death,” Oketch-Rabah said. “The FDA did the work and concluded that these products were adulterated and presented an unreasonable risk of illness or injury to the public.”
Concerns about the ephedra products extended beyond variation in alkaloid content to the possibility of undeclared or adulterating active ingredients.
More recently, the agency has issued warnings about dietary supplements adulterated with toxic yellow oleander, a botanical that has been linked to adverse cardiovascular effects. The latest warning letters, issued Sept. 17, added three supplement products to its safety alert, reminding consumers that toxic yellow oleander can cause neurologic, gastrointestinal and cardiovascular toxicity that may be severe or even fatal.
“These reported adverse effects, and there are many more that you probably read about, highlight the potential risk and the need to develop better safety evaluation methods,” Oketch-Rabah said.
“The current safety qualification process relies heavily on non-clinical testing and on traditional animal testing, and this is not well suited for botanicals. These methods are often insensitive to minor variations in complex mixtures. They are also resource intensive. They raise moral and ethical considerations. Therefore, we need tools that are more efficient and relevant for this unique product.”
Over the past year, the consortium’s work has been recognized by the European Food Safety Authority (EFSA) in guidance on botanical safety, while the BSC continues to advance new approach methodologies (NAMs) for assessing risks like hepatotoxicity and cardiotoxicity. Research published in Pharmaceutical Biology has covered topics ranging from the consortium’s activities to date to screening strategies for developmental, reproductive and dermal toxicity as well as the risk of herb-drug interactions.
