What are the side effects of polyphenols? Potential risks and concerns

October 13, 2025 •

4 min read

According to research published in the journal Molecules, it is possible for polyphenols to exert harmful effects depending on the dose and other factors. While a diet rich in polyphenols from whole foods is generally safe and beneficial, high-dose supplements may present a different set of risks, prompting the question: what are the side effects of polyphenols?.

Quick Summary

Excessive intake of polyphenols, primarily from supplements, can lead to adverse effects including impaired iron absorption, digestive upset, hormonal imbalances, and potential drug interactions.

Key Points

Iron absorption interference: High doses of polyphenols, particularly from supplements, can bind to non-heme iron in the intestines, reducing its absorption and potentially causing iron deficiency anemia.
Gastrointestinal distress: Excessive intake can lead to digestive side effects, including diarrhea, bloating, nausea, and abdominal pain.
Drug interactions: Polyphenols in concentrated forms, like those in grapefruit juice, can inhibit enzymes crucial for drug metabolism, potentially increasing drug bioavailability and toxicity.
Endocrine system disruption: Certain polyphenols, such as soy isoflavones, can affect hormonal balance and interfere with thyroid function, especially at high supplemental doses or in individuals with iodine deficiency.
Food vs. supplements: Polyphenols from whole foods are generally safe and effective, whereas high-dose supplements are not well-regulated and carry a higher risk of adverse effects.
Prooxidant activity: At unnaturally high concentrations, polyphenols can transition from antioxidants to prooxidants, potentially causing cellular damage and oxidative stress.
Vulnerable populations: Individuals with marginal iron stores, pregnant women, and those with nutrient deficiencies should be particularly cautious with high polyphenol intake from supplements.

Understanding the Double-Edged Sword of Polyphenols

Polyphenols are plant compounds celebrated for their antioxidant and anti-inflammatory properties, found naturally in fruits, vegetables, and teas. In their natural form, they are an integral and safe part of a healthy diet. The concern arises with concentrated polyphenol supplements, which can contain pharmacological doses far exceeding natural dietary intake and have not been consistently shown to offer the same benefits as whole foods. Research indicates that at these high doses, polyphenols can act as a double-edged sword, where their beneficial properties can turn into risks.

Adverse Effects of High-Dose Polyphenol Supplements

Impaired Iron Absorption

One of the most well-documented side effects of high polyphenol intake is the inhibition of non-heme iron absorption. Polyphenols can chelate (bind to) iron in the intestines, forming complexes that the body cannot easily absorb. This can be particularly harmful for vulnerable populations already at risk for iron deficiency, such as pregnant women and young children. A study found that consuming beverages with 100–400 mg of polyphenols could reduce iron absorption by 60–90%, and some supplement extracts, like grape seed, have been shown to significantly decrease iron transport.

Gastrointestinal Distress

Excessive amounts of polyphenols, especially from supplements, can trigger unpleasant digestive symptoms. This may be due to the polyphenols' effects on the gut microbiota or interference with digestive enzymes.

Possible symptoms: Diarrhea, constipation, abdominal pain, bloating, and nausea.
Mechanism: The interaction of polyphenols with proteins can inhibit digestive enzymes like amylase, lipase, and trypsin, leading to impaired digestion.
Supplements vs. food: Some studies suggest that certain foods rich in lectins, which can cause indigestion, have their adverse effects mitigated by soaking or sprouting. However, with highly concentrated supplements, this is not a factor.

Endocrine System Disruptions

Certain polyphenols, particularly the isoflavones found in soy, can exhibit weak estrogen-like or anti-estrogenic activity. High-dose supplements, therefore, may interfere with the endocrine system.

Thyroid function: Some flavonoids can inhibit thyroid peroxidase, an enzyme essential for thyroid hormone biosynthesis. This effect is more pronounced in cases of iodine deficiency.
Hormonal balance: High intake of isoflavones has been linked to potential reproductive and developmental issues in animal studies, with concerns about effects on sexual maturation in infants consuming high levels through soy-based formulas.

Potential for Prooxidant and Genotoxic Effects

While generally known for their antioxidant properties, very high concentrations of polyphenols can sometimes shift to acting as prooxidants. This can increase oxidative stress and potentially cause cellular damage, though this has been observed primarily in in vitro or animal studies using high concentrations. Some studies have also suggested potential genotoxic (damaging to DNA) and carcinogenic effects in animal models with excessive doses of certain polyphenols.

Drug Interactions

Certain polyphenols can significantly impact the metabolism of pharmaceutical drugs by inhibiting enzymes in the cytochrome P450 family.

Grapefruit juice effect: For example, polyphenols like naringenin in grapefruit juice can potently inhibit CYP3A4, an enzyme responsible for metabolizing many prescription drugs. This can increase drug bioavailability and potentially lead to toxicity.
Clinically significant drugs: Interactions can be particularly dangerous for drugs with a narrow therapeutic range, such as cyclosporine.

Navigating the Difference: Whole Foods vs. Supplements

It is crucial to distinguish between obtaining polyphenols from whole foods and taking concentrated supplements. The vast majority of research linking polyphenols to health benefits is based on dietary intake from plant-based foods, not supplements. The matrix of whole foods contains a complex mix of nutrients and fibers that can modulate the effects of polyphenols and are generally considered safe for most people. Supplements, on the other hand, deliver isolated compounds at unnaturally high doses, which are not subject to the same regulatory oversight as pharmaceutical drugs.

What to Consider Before Taking Polyphenol Supplements


Consideration	Whole Foods	High-Dose Supplements
Iron Absorption	Lower inhibitory effect due to typical intake levels and the presence of other nutrients like vitamin C.	Higher risk of inhibited absorption, potentially leading to iron-deficiency anemia in at-risk individuals.
Digestive Impact	Unpleasant symptoms like bloating or gas are possible, but less common and often manageable (e.g., by soaking legumes).	Increased risk of gastrointestinal issues such as diarrhea or stomach discomfort.
Drug Interactions	Rare, with the exception of specific interactions (e.g., grapefruit juice with certain medications).	Significant risk for interactions with medications metabolized by cytochrome P450 enzymes.
Endocrine Effects	Safe at normal dietary levels for most people.	Potential for disruption, especially with isoflavones and thyroid hormone biosynthesis, particularly if iodine is deficient.
Safety Profile	Generally considered very safe and beneficial for most individuals.	High doses carry a risk of toxicity, and long-term effects are not well-established.

Conclusion: Prioritizing Food Over Supplements

The key to avoiding the potential side effects of polyphenols lies in moderation and focusing on whole-food sources. A diet rich in fruits, vegetables, and teas provides a safe and effective way to benefit from these compounds without the risks associated with high-dose supplementation. For those considering polyphenol supplements, especially individuals with pre-existing health conditions, nutrient deficiencies, or those on medication, it is essential to consult a healthcare provider. The natural food matrix offers a complex and safe delivery system, while the isolated, concentrated forms found in supplements can disrupt nutrient absorption, cause digestive upset, and interact with medications in ways that are still not fully understood.

Visit the NIH website for more detailed health information.

Frequently Asked Questions

Yes, high intake of polyphenols, particularly from concentrated supplements, can impair the absorption of non-heme iron by binding to it in the gut. This can lead to or worsen iron deficiency, especially in vulnerable populations.

Polyphenol-rich foods are safe for most people, but the same cannot be said for supplements. High-dose supplements are not well-regulated and may cause side effects, unlike the moderate intake from a healthy diet.

Yes, consuming excessive amounts of polyphenols can lead to gastrointestinal side effects such as diarrhea, constipation, bloating, and abdominal pain. This can be due to their impact on digestive enzymes and gut bacteria.

Yes, some polyphenols, such as those found in grapefruit juice, can inhibit drug-metabolizing enzymes (e.g., CYP3A4). This can increase the concentration of certain medications in the body, potentially leading to increased side effects or toxicity.

Polyphenols from whole foods are consumed in safe, moderate amounts as part of a complex matrix of nutrients. Supplements, however, provide concentrated, high doses of isolated compounds that can behave differently in the body and pose higher risks.

Certain polyphenols, including some flavonoids and soy isoflavones, can interfere with thyroid hormone synthesis by inhibiting thyroid peroxidase. This is particularly a concern with high supplemental doses, especially in individuals with an iodine deficiency.

Although rare, some minor side effects reported with polyphenol supplementation include headaches, dizziness, and skin rashes. These effects are generally mild and transient.