In a wellness landscape where clinical studies are often treated as the gold standard, the reality is far more nuanced especially when it comes to supplements. In this edition of Ask Dr. Shilpa, we sit down with Dr. Shilpa Raut, Vice President of Research and Development at Cymbiotika, to unpack why supplement research can feel so inconsistent and what most people are getting wrong when they read headlines.

From the challenges of designing clinical trials for nutrients to the overlooked role of dosage, bioavailability, and delivery systems, this conversation pulls back the curtain on why some studies show little to no benefit and what that actually means for real-world use. She also gets into the difference between testing single ingredients versus finished formulas, and how to more intelligently evaluate whether a supplement is worth taking in the first place.

If you’ve ever wondered why “the science” around supplements feels contradictory, this is the clarity you’ve been looking for.

Clinical studies are often treated as the gold standard but when it comes to supplements, the picture feels less clear. Why do outcomes differ?

Some large trials and meta-analyses sometimes conclude that common supplements show little or no benefit. For example, a 2021 JACC review found no clear effect for commonly used multivitamins, vitamin D, calcium, and vitamin C on cardiovascular outcomes and all-cause mortality, and noted that conclusive benefit across different dietary backgrounds has not been shown when people are already nutrient sufficient. The VITAL trial similarly found that vitamin D did not lower cardiovascular events overall, and marine omega-3s did not lower major cardiovascular events or cancer overall in a generally healthy population. 

One question to ask is did these clinicals use products that we bioavailable? You can take the best bioactive ingredients on the planet — carotenoids, polyphenols, antioxidants, phytosterols — and still get almost none of their benefits. Not because the ingredients are wrong. Because the delivery form is broken

Another difference to consider is that drugs are usually tested to treat or manage a disease state, while supplements are generally positioned to support normal structure or function in healthy people. From a regulatory standpoint, dietary supplements are not intended to diagnose, treat, cure, or prevent disease; those are drug claims. That changes the type of population, endpoints, and claims a supplement company can study.

With drugs, you may be studying patients who clearly have a condition and a measurable clinical endpoint. With supplements, you are often studying healthy people or people who are “not sick enough” to qualify as patients. That means the expected effect size is often smaller, takes longer to detect, and is more influenced by baseline nutrition, lifestyle, sleep, stress, genetics, microbiome, and diet. Reviews on nutraceutical trial design have pointed out that nutrients are not like drugs: they work in networks, affect many tissues, and the body’s baseline nutrient status can strongly influence response. 

In a controlled study, participants are expected to follow instructions closely. In real life, that’s rarely the case. How much does consistency or user behavior impact outcomes? Do you think some supplements “fail” in studies simply because they require a level of compliance that’s hard to maintain outside a trial?

We see studies using very specific doses that don’t always match what’s in consumer products. How does dosing impact outcomes and why is it so hard to standardize?

Dosing is one of the most overlooked reasons why supplement studies and real-world results don’t align.

In clinical research, doses are carefully selected to reach a threshold where a biological effect is measurable. Many consumer products provide a fraction of that dose. For example, studies on Coenzyme Q10 often use 100–200 mg/day to impact energy metabolism and cardiovascular markers, whereas lower doses may not move the needle.

From a scientific standpoint, this comes down to:

• Dose-response relationships (you need enough to see an effect)

• Pharmacokinetics (absorption/ how much actually reaches circulation)

• Baseline status of the individual (deficient vs optimized)

Why is it hard to standardize?

• Human variability (diet, microbiome, genetics, age)

• Different chemical forms (e.g., magnesium oxide vs glycinate behave very differently)

• Poor absorption of many oral formats / delivery systems

So when a study “works” and a product doesn’t—it’s often not because the ingredient is ineffective, but because the delivered dose at the tissue level is insufficient.

You’ve spoken a lot about absorption. How much do bioavailability and delivery methods influence whether a clinical study shows a meaningful result?

This is arguably the most important—and most misunderstood—factor.

A supplement only works if it gets into the bloodstream in a usable form. That’s the essence of bioavailability.

Take fat-soluble nutrients like vitamin D or omega-3s. Studies show their absorption is significantly improved when taken with fat-containing meals (Dawson-Hughes et al., 2015). But in real life, meal composition varies widely—creating massive inter and intra subject variability in outcomes. Do you ever eat the same meal? 

Even more striking:

• Curcumin has extremely low natural bioavailability; human studies show minimal plasma levels unless enhanced delivery systems are used (Anand et al., 2007).

• Glutathione was long debated because standard oral forms showed inconsistent absorption—until newer delivery systems demonstrated measurable increases in blood levels 

• Nutrients like carotenoids, polyphenols, antioxidants are lipophilic. That means they're oil-based, and our stomach is water-based. Oil and water don't mix. So when you swallow a gummy or capsule, the ingredient is released into an environment it literally cannot dissolve into. The nutrient needs to have a good hydrophilic and hydrophobic balance in order to be rapidly absorbed and transported. Special delivery systems that provide a food-like matrix may be beneficial. surrounded by fats, proteins, fiber, and co-nutrients that make them stable, bioavailable, and effective

This is why many meta-analyses conclude “supplements don’t work.” In reality, what they often show is:

Poorly absorbed supplements don’t produce consistent clinical outcomes.

Why are most studies done on single ingredients when people take blends?

Because scientifically, it’s the only way to establish causality. Clinical trials are designed to isolate variables. If you test a blend of 20 ingredients and see an effect, you can’t answer which ingredient worked or Was there synergy? Was something counteracting something else?

Also, many clinicals are sponsored by ingredient suppliers and hence are studied on the single ingredient that they intend to sell. However people are not buying a single ingredient, they are buying a finished product. 

This creates a disconnect with real-world use, where people take blends or stacks.

From a formulation standpoint, this is where expertise matters:

• Some nutrients compete for absorption (e.g., minerals using shared transporters)

• Some are synergistic (e.g., vitamin D + K2)

• Some require different conditions (fat vs empty stomach)

Poorly designed blends—especially “kitchen sink” formulas with 20–60 ingredients—often lead to sub-therapeutic dosing , absorption competition or metabolic burden (especially on the liver)

Well-designed blends, on the other hand, are built intentionally around:

• Complementary mechanisms

• Compatible absorption pathways

• Clinically relevant dosing per ingredient

Before a nutrient can do anything for your body, it has to survive a gauntlet: manufacturing heat, months on a shelf, stomach acid, and a GI tract full of enzymes. Most bioactives in standard supplements don't make it through. Hence i cannot underscore the importance of testing the final finished product. 

If you were designing the ideal study for a supplement, what key elements would you insist on?

If the goal is to prove real-world efficacy and not just check a both, then  these are the non-negotiables:

1. Test the finished product, not just the ingredient
Most studies test raw ingredients, but consumers take formulations. Ingredients undergo processing and manufacturing steps to become a final finished product. Processing factors such as heat, temperature, and pressure directly damage the bioaccessibility of many nutrients for example carotenoids and polyphenols. The final delivery system can dramatically change outcomes.

2. Measure bioavailability alongside clinical endpoints
You need to show:

• Does it reach the bloodstream?

• Does it stay elevated over time?

• Does that translate into a physiological benefit?

3. Use the intended dose and format
No artificial conditions. Test exactly what the consumer will use.

4. Study a relevant population
Healthy adults vs diseased populations can yield very different results.

5. Include real-world variability
Diet, timing, and lifestyle factors should be accounted for—not eliminated—because that’s how people actually use supplements.

6. Track both short-term and sustained effects
Some nutrients act acutely (e.g., cognitive adaptogens), while others require weeks to show benefits (e.g., mitochondrial or structural changes).

In short, the ideal study bridges pharmaceutical rigor with real-world relevance.

For a reader who wants to be informed but not overwhelmed, what are the top 3 things they should look for when evaluating supplement claims?

If I had to simplify it down to three filters:

1. Is the dose clinically relevant?

Look for:

• Does the product match doses used in human studies?

• Or is it a “label dose” that sounds good but won’t drive outcomes?

2. Is the delivery system designed for absorption?

Ask:

• Does this nutrient require fat, specific timing, or protection from degradation?

3. Is the claim based on the ingredient or the finished product?

Many brands cite studies on ingredients, not their actual formulation. Ingredient science and claim is crucial and the foundation for a good product. But, it is even more important to test the final finished formula. A clinically studied ingredient does not guarantee a clinically effective product. The gold standard is evidence on the finished product at the delivered dose and format.