Can natural supplements backfire? Review explains how and why

Can natural supplements backfire? Review explains how and why

A new review captures how natural supplements can both protect and threaten health, depending on dose, duration and delivery - and points to next-generation technologies as the key to unlocking their full therapeutic power.

In a recent review in the journalLimits in nutritionResearchers collected and summarized more than 120 publications to elucidate the dual therapeutic and toxicological effects of nutraceuticals. The overview highlights revenue from preclinical and clinical studies focused on curcumin (CUR), piperine (PPR), resveratrol (RSV), and quercetin (Que) between 2015 and 2024.

The study results show that while all nutraceuticals evaluated have medically beneficial protective and therapeutic effects, they each come with their own side effects associated with higher dosages, highlighting the need for science-based guidelines aimed at managing interactions and improving the benefits of nutracuticals without subjecting patients to their negative effects. The review further suggests innovations such as nanocapsulation and AI-guided delivery systems that could help achieve these goals.

background

Nutraceuticals are foods or food derivatives that serve not only as sources of essential nutrition but also as pharmacological benefits. These include nutritional supplements, herbal medications and probiotics. While the term “nutraceutical” (“nutrition” and “pharmaceutical”) is relatively new, the concept dates back hundreds or even thousands of years.

Nutraceuticals gained popularity worldwide due to their organic origin and lower side effects compared to conventional synthetic drugs. However, a growing body of literature suggests that bioactive nutraceuticals, when consumed out of context (without a prescription) or at higher doses or in specific populations, pose medical challenges. This requires a scientifically sound understanding of the benefits and drawbacks of nutraceuticals along with a case-specific, balanced consumption plan to maximize the pharmacological benefits of these supplements with minimal risk.

“The growing interest in nutraceuticals is based on their potential to address chronic diseases such as cardiovascular disease, neurodegenerative diseases and metabolic syndromes, which are often associated with oxidative stress and inflammation.”

The positive benefits of nutraceuticals are well documented. Unfortunately, given their relative newness, the literature remains relatively scarce on the long-term effects of nutraceuticals, particularly their toxicity with prolonged use, bioavailability, and interactions with conventional medical interventions. The review also highlights the lack of a globally harmonized regulatory framework for nutraceutical purity, labeling and safety claims.

About the rating

The present review aims to collect and summarize existing scientific knowledge on nutraceuticals in order to elucidate two main topics: the mechanisms that determine the therapeutic and toxicological effects of nutraceuticals and recommendations for the safe and effective use of these dietary supplements. The review aims to guide clinicians, policymakers, researchers and consumers on when and how to use nutraceuticals effectively, maximizing their benefits while minimizing potential harms.

The review focuses on four widely used nutraceuticals: resveratrol (RSV), a polyphenolic compound found in grapes and grape products; Curcumin (CUR), a bioactive obtained from turmeric (Curcuma longa); Piperine (PPR), obtained from black pepper; and quercetin (Que), a flavonoid found in several fruits and vegetables.

Publications of interest were obtained from three online repositories (Scopus, PubMed and Web of Science) using a custom keyword search. Title, abstract and full text screening shortlisted ~120 publications for inclusion, only studies with clinical relevance, methodological rigor and mechanistic insights were included.

Resveratrol

Resveratrol can re-engineer gut bacterial populations and indirectly reduce systemic inflammation, a finding that links dietary habits to chronic disease management.

RSV is gaining scientific interest due to its wide-ranging therapeutic benefits, including cardiovascular, metabolic, neurological, pro-apoptotic and anti-inflammatory. In particular, the bioact reduces oxidative stress, improves lipid metabolism and reduces blood pressure. It has even been clinically validated to improve cognitive function and delay Alzheimer's disease (AD) progression. However, RSV has hormetic effects - protective at low doses but harmful at high doses - and studies showing toxicity at elevated concentrations, including renal impairment and thyroid dysfunction. Chronobiological differences in RSV administration have also been observed, with some evidence suggesting that time of day may influence lipid peroxidation and drug metabolism.

Curcumin

The effects of curcumin on thyroid function appear to be age-dependent, with studies showing altered hormone levels in older adults but minimal effects in younger populations.

Cur is arguably the most studied antioxidant and anti-inflammatory in this review, routinely used to treat diabetes, arthritis, and cardiovascular diseases (CVDs). It also targets multiple oncological pathways and demonstrates significant neuroprotective benefits. The interference of CUR with CVD drugs (e.g. amlodipine) occurs through modulation of CYP3A4 and P-glycoprotein (P-GP) levels and highlights the importance of complete health profile assessments before its use. Emerging evidence also notes potential effects on thyroid hormone levels and reproductive function in animal models, particularly at high doses or via nanoparticle delivery systems.

Piperine

Inhibition of the enzyme UDP-glucuronosyltransferase by piperine may prolong drug activity—a benefit for therapies but a risk for toxicity with medications such as blood thinners.

PPR is widely used as a supplement and adjuvant known for its anti-inflammatory, antioxidant stress, neuroprotection and bioavailability properties. Preclinical studies report reproductive toxicity in rats at doses greater than 10 mg/kg, as well as risks of improving side effects of drugs such as carbamazepine and warfarin. Emerging evidence also links prolonged high-dose PPR to impaired cognitive performance in animal models and highlights the importance of understanding and educating the target patient prior to their prolonged consumption. Recent data also show tissue-level changes and potential organ-specific toxicity in rodent models receiving higher doses.

"A hallmark of PPR is its ability to expand the bioavailability of drugs and nutrients. By inhibiting drug-metabolizing enzymes (EG, cytochrome p450, UDP-glucuronosyltransferase) and significantly increasing intestinal absorption, inhibits PPR-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admin-admining (p-gp) and RSV, which it is considered a critical addition in nutraceutical formulations position.”

Quercetin

In laboratory studies, quercetin binds to heavy metals such as lead and cadmium, indicating its potential as a detoxifying agent alongside its antioxidant properties.

Que is often obtained naturally, derived from the consumption of onions and apples. Hallmark effects include free radical neutralization, mitigation of oxidative stress and improvement of cellular integrity, making it hailed as a potential treatment for cancer, cardiovascular disease (CVD) and aging. While Que synergizes with certain chemotherapy drugs (e.g., methotrexate) to enhance anti-inflammatory effects, it may also interfere with drugs such as cyclosporine. High-dose queue preparations have been associated with pro-oxidant activities and organ damage in preclinical studies. The aglycone form found in dietary supplements shows greater bioavailability but also a higher probability of interacting with metabolizing enzymes and transporters.

Summary and future directions

This review provides extensive detail on the pros and cons of four of the most popular nutraceuticals available, highlighting their therapeutic and pharmacological benefits while warning of potential dose- and interaction-dependent side effects.

It further suggests that emerging technologies such as nanoencapsulation will improve the targeted delivery and bioavailability of these nutraceuticals, reduce off-target toxicity, and ensure that these bioactives reach their target organs or tissues to maximize their benefits and mitigate their costs. Additional innovations discussed include in silico molecular docking to predict drug-target interactions, nutrigenome tools to personalize interventions, and the Nutraceutical Interaction Risk Score (NIRs) to stratify patients by potential toxicity.

"...While nutraceuticals are a valuable tool for promoting health and preventing disease, their full potential can only be realized through rigorous scientific research, personalized dosing strategies, and a comprehensive understanding of their benefits and potential risks. Exploring the integration of nanotechnology and smart materials has proven to be a transformative approach to improving the effectiveness and safety of nutritional nutrients."

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