Double-blind, randomized, placebo-controlled trials are the culmination of centuries of medical progress. Here’s how Seed is using them to add legitimacy and rigor to the probiotic space.

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Written by Seed’s Scientific Communications Team
Reviewed by Jennie O’Grady: Senior SciComms Specialist at Seed

Like so many scientific breakthroughs, the first clinical trial happened totally by accident. In 1537, French surgeon Ambroise Paré ran out of the treatment he usually gave to soldiers wounded in battle (boiling oil, in case you were wondering). In a moment of desperate experimentation, he applied an ointment of egg yolks, rose extract, and turpentine to some soldiers instead—and noticed that it reduced inflammation and swelling even more than the original treatment.1 

Since Paré’s day, physicians and researchers have gradually added more depth, rigor, and integrity to the clinical testing process. The word “placebo” was formally defined in the Medical Dictionary of 1811 (“an epithet given to any medicine more to please than benefit the patient”) and the first double-blind trial (where neither the patients nor the physicians knew who had been assigned treatment) was conducted on patulin, a potential treatment for the common cold, in 1943.1,2 This has led us to the modern-day gold standard of testing: the double-blind, randomized controlled trial (DBRCT). 

Read on to learn why this type of research is the culmination of centuries of medical progress—and how Seed is using it to add legitimacy and rigor to the probiotic space.

Breaking Down Double-Blind, Randomized Controlled Trials

A DBRCT is a type of scientific study designed to test the effectiveness and safety of a treatment (such as a drug or supplement) as objectively and rigorously as possible. “If you want to ensure safety as well as efficacy, double-blind, randomized, placebo-controlled trials are by far the best way to do so,” says Nicholas Rivera, Seed’s Senior Manager of Regulatory Affairs.

DBRCTs have three key components that make them more reliable than other study designs. They are:

  • Double-blind: In a double-blind trial, neither the participants nor the researchers know who is receiving the treatment and who is receiving a placebo (as opposed to single-blind trials, in which researchers know who received what treatment). This prevents anyone from developing a bias that could influence the study’s results.
  • Randomized: Randomized trials are—no surprise here—random! Participants are randomly assigned to either a treatment group (that receives the active intervention) or a control group (that receives a placebo or another treatment). Factors like age, gender, and health status are balanced between groups. This randomization helps prevent selection bias and ensures the groups are comparable.
  • Controlled: In a DBRCT, the group receiving a placebo is the control group. Researchers compare the control group to the treatment group in order to determine which results are due to the treatment itself. Without controlling a study, you can’t definitively say whether a treatment works or if it just appears to work due to psychological factors (like the placebo effect) or natural changes over time.

In the medical space, DBRCTs are essential for minimizing biases in behavior, expectations, or reporting that could influence results. The use of a placebo is especially crucial, as some studies have shown that a placebo can be just as effective as a treatment, especially when it comes to pain or other subjective measures.3

“Your body has a physiological response to placebos, which can influence specific neurotransmitters such as dopamine.4 This may actually result in some sort of physiological change that makes someone feel better,” explains Rivera. “So controlling for that kind of effect is extremely important.”

The structure of DBRCTs also makes them easier to replicate in future studies. Over time, consistent findings across multiple DBRCTs strengthen the scientific evidence and credibility of a treatment.

How Common Are They? 

It’s easy to assume that all supplements have been the subject of at least one DBRCT or that, at the bare minimum, they’ve undergone clinical testing on actual people. This isn’t necessarily true.

While pharmaceutical companies are often required by regulatory bodies like the FDA to conduct clinical trials on humans, supplement companies are not under the same obligation (since, unlike pharmaceuticals, they are not approved by FDA and are not intended to cure, treat, or prevent disease). 

By the Numbers

As of this year, there were 16,756 registered clinical trials on dietary supplements—and as many as 100,000 supplements on the market.5 This means that roughly 16.7% of the supplements you see on shelves (at most) have been clinically tested.

Instead of conducting their own testing, most supplement companies will rely on existing research for the individual ingredients in their products (which could have been conducted on people, animals, or cell cultures). This leaves the possibility that their ingredients won’t confer the same benefits when combined, or that their impacts will differ from person to person. 

This explains why language like “Contains ingredients shown to XYZ” is such a common parlance in the supplement space. “Those qualifiers are in there by design, to ensure that consumers are not interpreting that the finished product has been tested for those specific health outcomes,” says Rivera. 

Supplement companies don’t do this to cause harm or intentionally mislead consumers. In reality, conducting clinical tests, particularly DBRCTs, is expensive, resource-intensive, and time-consuming. It’s an onerous process that involves coordinating with multiple organizations, doing rounds of iterative testing, and working through a maze of (justly placed) red tape. For most companies, particularly smaller companies or those that are newer to market, it’s just not worth it. But Seed is setting a different standard.

When we set out to put our flagship product, DS-01® Daily Synbiotic, through multiple double-blind, randomized controlled trials back in 2020, we knew we were in for a long and complicated process. But we felt that the probiotics category deserved such rigor and transparency, and we were confident enough in DS-01® to place it under the highest level of scientific scrutiny.

The Seed Difference

Over the last four years, we’ve conducted two randomized, double-blind, placebo-controlled trials to paint a more complete picture of how the 24 strains in DS-01® work in unison. After designing protocols, receiving approvals, finding participants, collecting data, analyzing results, and summarizing findings (phew!), we’re excited to present these high-level findings from our latest research:

  • DBRCT 1: The first clinical trial involved 103 adults who presented with mixed digestive symptoms. At the start of the study, participants’ gut microbiomes were analyzed using fecal testing. Certain immune response biomarkers were also collected. Throughout the 12-week double-blind trial, one group of participants took a serving (2 capsules) of DS-01® daily, while the other group took placebo capsules. Both groups were invited to track their day-to-day gastrointestinal comfort using a smartphone app. At the end of the study, those in the DS-01® group experienced significant improvements in abdominal discomfort and measures of occasional constipation including bowel movement frequency and stool consistency. Follow-up testing also showed that DS-01® promoted the 400% population growth of Bifidobacterium and Lactobacillus in the gut.6 This tells us that DS-01® supports comfortable and regular bowel movements in people who experience digestive discomforts and supports the growth of health-promoting gut microbes.*
  • DBRCT 2: Thirty-two healthy adult participants were recruited for the second clinical trial. At the start of the study, they experienced seven days of gastrointestinal stressors, which reduced the composition of the beneficial microbes in their guts. Then, for the next 12 weeks, one group of participants took a serving (2 capsules) of DS-01® daily and the other group took placebo capsules. Researchers analyzed their gut microbiomes at the beginning and end of the treatment period. The results showed that DS-01® enhanced the population of beneficial Lactobacillus microbes (up to 90% higher than placebo), and Bifidobacterium microbes (up to 76% higher than placebo) in the gut following the disruptor, while maintaining baseline microbiome diversity. Those who took DS-01® had a 49% improvement in long-term gut barrier integrity and showed higher levels of certain metabolites like Urolithin A—a powerful molecule for healthy aging.7 This tells us that DS-01® promotes gastrointestinal resilience and supports healthy gut barrier function following temporary disruptors.*

These results join our already robust collection of over 20 clinical and pre-clinical studies on DS-01® ingredients, further showing that the probiotic and prebiotic formula offers an effective way to improve gut (and whole-body) health daily.*

At Seed, we continue testing our products long after they are released. Conducting clinical trials is just another way we add reputable science to the (often misrepresented) probiotic and microbiome landscape.

EXPLORE FURTHER: So, You Just Started DS-01®. Now What?

The Key Insight

Double-blind, randomized controlled trials (DBRCTs) minimize the risk of bias in the scientific process and lead to more accurate and replicable findings. Seed is one of the few probiotic companies conducting DBRCTs on our products.

The microbial world within us is vast, dynamic, and critically understudied. We hope that by conducting pioneering probiotic and microbiome research, we inspire other companies in our space to do the same.

Citations

  1. Bhatt A. (2010). Evolution of clinical research: A history before and beyond James Lind. Perspectives In Clinical Research, 1(1), 6–10.
  2. de Craen, A. J., Kaptchuk, T. J., Tijssen, J. G., & Kleijnen, J. (1999). Placebos and placebo effects in medicine: Historical overview. Journal of the Royal Society of Medicine, 92(10), 511–515. https://doi.org/10.1177/014107689909201005
  3. Howick, J., Friedemann, C., Tsakok, M., Watson, R., Tsakok, T., Thomas, J., Perera, R., Fleming, S., & Heneghan, C. (2013). Are treatments more effective than placebos? A systematic review and meta-analysis. PloS one, 8(5), e62599. https://doi.org/10.1371/journal.pone.0062599
  4. Munnangi, S., Sundjaja, J. H., Singh, K., Dua, A., & Angus, L. D. (2023, November 13). Placebo effect. StatPearls – NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK513296/
  5. Research, C. F. D. E. A. (2024, March 5). FDA’s Regulation of Dietary Supplements with Dr. Cara Welch. U.S. Food And Drug Administration. https://www.fda.gov/drugs/news-events-human-drugs/fdas-regulation-dietary-supplements-dr-cara-welch
  6. Napier, B. A., Van Den Elzen, C., Al-Ghalith, G. A., Avena, C. V., Gevers, D., Dhir, R., Nee, J., Lembo, A., & Simmons, S. L. (2024). MO1894 A MULTI-SPECIES SYNBIOTIC (DS-01) ALLEVIATES CONSTIPATION AND ABDOMINAL PAIN IN IRRITABLE BOWEL SYNDROME SUBTYPE MIXED (IBS-M) SUBJECTS WHILE BOOSTING SYNBIOTIC SPECIES ASSOCIATED WITH DECREASED SYSTEMIC INFLAMMATION AND NET FORMATION. Gastroenterology, 166(5), S-1164. https://doi.org/10.1016/s0016-5085(24)03133-0
  7. Napier, B. A., Van Den Elzen, C., Al-Ghalith, G. A., Tierney, B. T., Evans, M., Stuivenberg, G., Reid, G., Gevers, D., Dhir, R., Mazmanian, S., Versalovic, J., Fasano, A., Blaser, M. J., & Simmons, S. L. (2024). MO1898 DAILY SUPPLEMENTATION WITH a MULTI-SPECIES SYNBIOTIC (DS-01) DURING AND AFTER ANTIBIOTIC TREATMENT PROTECTS AGAINST THE LOSS OF LOW-ABUNDANCE BACTERIAL SPECIES WHILE ENHANCING GUT BARRIER INTEGRITY. Gastroenterology, 166(5), S-1165. https://doi.org/10.1016/s0016-5085(24)03137-8