The panel:

William A. Chioffi, COO, Nammex, Calgary, AB, Canada and Asheville, NC, www.nammex.com

Nena Dockery, Scientific Affairs Manager, Stratum Nutrition, Carthage, MO, https://stratumnutrition.com

Annie Eng, CEO, HP Ingredients, Bradenton, FL, https://hpingredients.com

Shaheen Majeed, Global CEO & Managing Director, Sabinsa, Salt Lake City, UT, https://sami-sabinsagroup.com

James Roza, Chief Scientific Officer, Layn Natural Ingredients, Irvine, CA, https://layncorp.com

Mark G. Walin, Senior Vice President of Business Development & Marketing, BIO-CAT, Troy, VA, www.bio-cat.com

Science is where the rubber hits the road, especially if it is clinical research. In fact, science, quality and efficacy are the main differentiators in a crowded field of natural ingredients and products.

Here to help us sort it all out is a panel of industry experts.

NIE: Has the importance of human clinical research into natural ingredients become recognized much more widely than in years past?

Walin: Absolutely. The natural ingredient industry was once referred to as the “Wild West”—where poorly substantiated science persisted for far too long. The emergence of educated and empowered consumers who demand information to make informed health decisions currently coincides with unprecedented industry investment in regulatory diligence and randomized, placebo-controlled clinical trials to ensure ingredients are both safe and efficacious. Finished product manufacturers now expect natural ingredient suppliers to bring peer-reviewed, published clinical trial results to the table.

Chioffi: Through the lens of the “post-pandemic” mindset of consumers, experts, such as Yadim Medore at Pure Branding, say that clinical research along with transparency are much more of an influence to purchase one product over another. At the product development level, I still see the main aim of brands as substantiation of structure function claims with some level of care given to safety. In vitro toxicity assays are widely available, and the Botanical Safety Consortium is using these types of in silico models to assess common safety risk assessment.

Dockery: Human clinical research, particularly randomized controlled trials (RCTs), have become much more widely used within the natural products industry. Clinical trials are more expensive in both time and resources than animal or cell studies, but they provide information that cannot be obtained from non-human studies. In addition, the FTC (Federal Trade Commission) requires the use of clinical trials to substantiate ingredient or product claims. Clinical trials can also provide at least the perception of greater safety and efficacy to potential distributors and the end-consumer, especially for lesser known or new ingredients.

Roza: Yes, the value of human clinical data has increased immensely as the supplement industry has grown and prospered. While many hypotheses look good on paper; showing proof of concept in a well-designed, double blind, placebo-controlled study gives credence to an ingredient’s efficacy. Relying on anecdotal or folkloric evidence of an ingredient’s worth falls short of the data to make a compelling case for its use as a supplement.

Eng: The importance of demonstrating efficacy through human studies has never been stronger, or more necessary. We have 25 published human studies on LJ 100, 12-plus for Bergamonte, five for ParActin, two for IQ200, and more, which validates our slogan, “Where Science Never Sleeps.”

Majeed: Human clinical research into natural ingredients has always been important, but today it’s become essential. Decades ago, Sabinsa was one of very few ingredient suppliers to conduct and publish human clinical trials, but it’s less rare today. This shift reflects a broader industry move toward authenticity and scientific substantiation, driven by the demands of consumers, and brands for research-based ingredients, and regulatory agencies for health claims validation. The increasing number of published human clinical trials and other research articles underscores the commitment to ensuring that our ingredient products meet rigorous scientific standards and are backed by peer-reviewed evidence.

NIE: Has the problem of companies using borrowed science become less of a problem? Please discuss.

Roza: Regarding borrowed science, that’s a dicey subject because one could argue that the data collected on a molecularly “pure” ingredient used in a human clinical could conceivably be used by another company claiming to have the same purity because it’s “exactly” the same. On the surface that may seem to be true but that doesn’t consider how it was produced or formulated. Likewise, just because a botanical extract is standardized to the same compounds as a botanical extract used in a clinical study doesn’t mean that it will have the same efficacy for the same reason. Piggybacking on research done by others is still very prevalent today, so it’s incumbent on manufacturers to thoroughly vet an ingredient before ascribing any benefits or claims based on the appropriate research that has been done.

Chioffi: Unfortunately the trend continues and the FTC has taken notice. The Federal Trade Commission’s direct communication to over 700 companies in April of 2023 regarding claims substantiation was to serve as a warning, and in general I have found the structure/function claims process more nebulous than other regulatory provisions. This communication was not calling out bad actors, but the general practice of how claims are substantiated. There are bad actors in every industry along with the good, and “borrowing” science is sadly still commonplace with the marketing of dietary supplements in general.

Eng: It is a bigger problem since now we have many newcomers in the industry who are experts in internet marketing but unfamiliar with the dietary supplement rules and regulations. We have tested several of these products from Amazon and unfortunately more than 50 percent of the products are either adulterated or do not contain the actives they claim to have. These companies are more than happy to borrow our science to make marketing claims. We usually try to reach out to these companies to give them an education about the science of our ingredients. Unfortunately, most of them are not interested in switching to our more expensive but clinically validated and safe ingredients. We usually ask them to take down our research information claims or send them a cease-and-desist order.

Dockery: Unfortunately, the use of borrowed science is still a problem within the industry, especially for popular ingredient categories. Borrowed science does have its place in providing extra support for a class of ingredient. For example, traditional use information or research on generic turmeric or 95 percent curcumin might be used as historical or background information or supporting science for a unique high-absorption form of curcumin, but it does not in any way alleviate the need for studies on the specific high-absorption form; and research on one form of high-absorption curcumin cannot provide support for another high-absorption form. Ingredients that are processed differently are dissimilar and may behave differently in the body.

The use of borrowed science is particularly problematic in the probiotics industry. Different strains of microorganisms can behave very differently in the body, so studies using a unique strain of probiotic bacteria should not be used to support the efficacy of different strains of the same bacterial species.

NIE: Are we right in assuming that most science on ingredients is done by suppliers to support claims for their proprietary branded ingredients? What about science on finished products with many ingredients?

Walin: Yes, it is correct to assume that if clinical research is going to be done, it will be done by the ingredient supplier. That doesn’t mean that finished goods suppliers won’t do their own clinical research on the final product as a whole, but by having science-backed ingredients in their products, branded marketers can feel much more secure in putting a product on the market using the data provided by the suppliers. As well, by having clinically backed products to support their claims, ingredient suppliers can more quickly and easily get into branded products. What we’re seeing now is the development of natural ingredients with decades of science being extended into other health benefits.

For finished products with multiple ingredients, suppliers and brands should work closely together to evaluate any potential negative impacts of combining ingredients to make sure that single ingredients are still delivering benefit. In some cases, a brand may see value in developing such a composition of ingredients to deliver additive or synergistic benefits.

Roza: Yes, the basis for any claims should rest on the research that has been done on that ingredient whether it be in vitro, in vivo or ex vivo and represented as such. Claims for a formula with multi-ingredients are complicated because you not only have to establish the efficacy of the individual ingredients but also how they should work synergistically to provide a desired result. Many formulas sold as supplements have not been clinically tested and must rely on second- or third-party information to make their claims.

Chioffi: Yes. The analytical chemists are still developing validated methods of analysis for single natural ingredients starting with purity, integrity and potency testing. Testing in a complex matrix of a finished oral dose form presents many challenges, though it has been accomplished. The main weak point of many otherwise well conducted clinical studies on plants and mushrooms is the lack of characterization of the starting materials. This leaves the researchers trying to replicate the science grasping at straws in order to do so with the lack of information present in the “materials and methods” sections of the studies for what was actually administered in the study.

NIE: Ingredients are only as good as how well they are absorbed, correct?

Roza: Yes, not only how well they are absorbed (pharmacokinetics) but how well they work once they enter the blood stream at a cellular level (pharmacodynamics). One of the major issues with a lot of ingredients is their solubility and dissolution time once it enters the gastric environment. Using resveratrol once again as an example, its solubility is poor and it’s estimated that only a percent or two is absorbed after digestion. Finding ways to improve the absorption of ingredients such as this through delivery systems that will increase its solubility helps improve absorption. Layn, in collaboration with our European partner, has developed a patented process using mesoporous silica to improve the solubility and absorption of poorly soluble ingredients such as resveratrol. Utilizing a proprietary milling process, we’re able to incorporate resveratrol into the nano-sized pores of silica derived from organic bamboo leaf and thereby increase its absorption by four times based on in-vitro and in-vivo animal studies that we have conducted.

Chioffi: In general, this is an accurate statement and the best of clinicians would likely address digestive weaknesses which lead to an overall disruption in the optimal nutrient absorption process. To know the true absorption of any ingredient via analytical methods (let’s say it’s an individual molecule for this question or even a group of molecules like triterpenoids) is very expensive. Unless it’s being marketed as a drug, a dietary supplement has no regulatory obligation to prove absorption in any manner, yet mimicked gut digestion and dissolution studies can be effective at an educated guess for proper conditions for absorption. It costs a minimum of $164 million in R&D to develop a drug, maybe a little less for a botanical drug. These do require detailed pharmacokinetic studies to be conducted.

Nammex does not make any structure function or health related claims though we do have branded ingredients. Our quality assessment (certificate of analysis) of the product stands as the scientific validation of purity, strength and authenticity for our certified organic mushroom extracts.

NIE: How important are sustained-release ingredients for your formulas?

Roza: Sustained releasing of an ingredient allows the ingredient to be absorbed over a longer period of time and makes it less vulnerable to first-pass metabolism. This is particularly effective for a complex formula, such as a multivitamin that has a large array of nutrients—some of which are water soluble, others that are lipophilic, and lastly may have minerals, botanicals or proteinaceous material that can cause interference. Some sustained release formulas have two stages. The first dissolving in the stomach (acid) and the second in the large intestine, which is alkaline.

NIE: In a study published on July 17, 2024, in JAMA Network Open allegedly only 11 percent of nearly 60 tested supplements provided the amount of key ingredients listed on the label. Was this a fluke? How do you ensure accuracy between labels and the actual product?

Roza: This could be due to many factors. I’ll take the high road first. A formula that has many ingredients can be subject to matrix interference once the finished product has been tested after it has been combined with binders, fillers and other excipients, which are part of the manufacturing process. Once these ingredients are all compressed or encapsulated, it is difficult to separate them apart and the individual components can obscure it from being accurately detected or quantified. Taking a lower route—the ingredients used may have been adulterated, inadequately tested, poorly formulated or mislabeled, just to name a few. The onus is on the manufacturer to ensure that each ingredient used has been properly identified, tested for potency/purity, and that the proper overages have been included to ensure that the product means label claim by the end of its best used date.

To ensure that the label and the actual product are accurately aligned, a manufacturer can utilize a qualified third-party laboratory to verify that the testing done in-house is accurate. This requires sharing methodologies so that both parties are comparing apples to apples and both labs are following good lab practices (GLP). Also, as a part of good manufacturing practices, stability testing either accelerated or real-time are required to detect any loss of potency that could occur over time.

Chioffi: We ensure accuracy through third party testing using multiple methods of analysis for GMP (good manufacturing practice) quality assessments for purity, identity and strength. We’ve been delighted with Purity IQ’s NMR program for identity testing and were honored to help them by providing authenticated reference materials for the mushroom species included in their transparent identity assessment and certification. Our laboratory partner for validation and authenticity of our mushroom products is Purity-IQ.

They utilize fit-for-purpose analytical tools: for mushroom authentication they use Nuclear Magnetic Resonance. The strength of this partnership is also supported by Purity-IQ’s investments in expertise, collaborative approach, industry experts and regulatory consultants. We are also engaging in a customer-facing product certification program with them.

NIE: Very briefly, please outline the latest science on your main proprietary branded ingredients.

Roza: SophorOx, a polyphenolic preparation, derived from the buds of the Sophora japonica plant has been demonstrated to inhibit oxidative stress and pro-inflammatory cytokines in three published studies (in-vitro, in-vivo and human clinical) by measuring key bio-markers responsible for both free radical production and inflammation.

Bio+Resveratrol utilizes a patented process for improving the dissolution and absorption of resveratrol using mesoporous silica to increase its solubility by more than four times. This has been demonstrated through in-vitro and in-vivo testing. This process can also be applied to other difficult-to-absorb ingredients such as curcumin or astaxanthin.

Eng: A new study demonstrated that our signature ingredient, LJ100 Tongkat Ali, is effective at increasing testosterone while simultaneously reducing cortisol in a low 100 mg dose. This study, published in Andrology, supports two previous studies arriving at the same conclusion. In this clinical trial, 30 healthy younger males aged 26 to 52 performed a 24-hour mountain bike event. The participants consumed either a 100 mg dose of LJ100 or placebo half-hour prior to the event and provided eight saliva samples to test for levels of testosterone and cortisol. The researchers found that cortisol levels were lower in the supplement group compared with the placebo group while the testosterone levels were higher.

Cortisol levels were 32.3 percent lower in the LJ100 group compared to placebo, while testosterone levels were 16.4 percent higher in the LJ100 group compared to placebo. Additionally, the participants who supplemented with LJ100 anecdotally reported feeling less fatigued.

Walin: BIO-CAT has developed and published a process that we utilize to perform predictive in-vitro gastrointestinal modeling prior to investing in human clinical trials. The clinicals are then performed by CROs or academic institutions that are renowned in the scientific discipline we’re investigating. This approach allows us to enter the clinical phase with an understanding of the probability of technical/scientific success allowing us to start the process of determining potential claims and product positioning applications.

A great example of utilizing both approaches is the 2022 NIE award winning OPTIZIOME P3 HYDROLYZER, a proprietary mixture of three microbial protease enzymes designed to enhance dietary protein digestion and complement a range of branded protein powder products. In-vitro gastrointestinal modeling showed release of 228 percent more branched chain amino acids from plant proteins and 73 percent more branched chain amino acids from whey protein. We then advanced OPTIZIOME P3 HYDROLYZER to clinical investigation at the University of Illinois Urbana-Champaign. In this randomized, placebo-controlled crossover trial of 24 healthy adults, P3 HYDROLYZER showed promising results in enhancing protein digestion, evidenced by increasing circulating amino acids up to 36 percent compared to placebo within two hours of consuming a protein shake.

NIE: How does your company convey the science behind your ingredients to consumers?

Roza: At Layn Natural Ingredients, we prioritize transparency and education. For instance, our comprehensive white paper on SophorOx, detailing all research including in-vitro, in-vivo and human clinical trials, is available on our website and through media channels. We also ensure that all studies are accessible on PubMed for credibility.

We use various marketing strategies, such as presentations, educational videos, and whitepapers, to reach a wider audience and provide insights into our ingredients. Additionally, we participate in industry conferences and trade shows to present our latest research findings and engage with professionals. Our goal is to empower manufacturers and consumers with knowledge, enabling informed decisions about our products through transparent and accessible scientific information.

NIE: What would you like to see, industry-wide, to promote responsible use of science in developing branded ingredients or supporting ingredients that have already been developed?

Walin: A huge issue in the industry right now is sourcing. The industry should be using responsibly sourced ingredients from reputable countries of origin. BIO-CAT primarily sources our enzymes from Japan, which has been recognized as the No. 1 Brand Index country for 10 years running. Additionally, our 40 strains of bacillus that we produce for the industry are manufactured in our vertically integrated fermentation facility in Shakopee, MN. By sourcing from credible countries vs. those where FDA (U.S. Food and Drug Administration) oversight/reach/frequency is limited will help the industry provide safer and more consistent quality products to consumers.

Eng: Clarity and transparency. For example, there is a plethora of studies using generic materials to further understanding of how the active compounds work. And then, there are the studies supported by the ingredient companies on their proprietary end ingredients made from the generics. So, when citing claims, simply distinguish between what is generic and what is proprietary, then ensure that the link or commonality between the two is clearly defined. This helps brand marketers to create truthful, non-misleading brand stories.

Majeed: It would be beneficial to see more stringent regulations and standards for scientific validation of branded ingredients. This includes mandatory clinical trials for proprietary ingredients, increased transparency in reporting study results, limited use of third-party literature, and enhanced collaboration between researchers and industry stakeholders. Such measures would promote responsible use of science, ensuring that products are both effective and trustworthy.

Roza: Guidelines created by the nutraceutical industry would be an excellent step forward to resolving this issue along with more education and industry involvement. Sadly, there are more observers than doers and unless we take ownership of this problem, it will continue to persist. NIE

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