A new review uncovers how common natural supplements can both protect and endanger health, depending on dose, duration, and delivery—and points to next-gen technologies as the key to unlocking their full therapeutic power.
Review: The double-edged sword of nutraceuticals: comprehensive review of protective agents and their hidden risks. Image Credit: Light Stock / Shutterstock
In a recent review in the journal Frontiers in Nutrition, researchers collated and summarized more than 120 publications to elucidate the dual therapeutic and toxicological effects of nutraceuticals. The review highlights the proceeds of preclinical and clinical studies focusing on curcumin (CUR), piperine (PPR), resveratrol (RSV), and quercetin (QUE) between 2015 and 2024.
Study findings reveal that while all evaluated nutraceuticals provide medically beneficial protective and therapeutic effects, each comes with its own side effects, particularly at higher dosages, highlighting the need for scientifically sound guidelines aimed at managing interactions and enhancing the benefits of nutraceuticals without subjecting patients to their adverse effects. The review further suggests innovations such as nanoencapsulation 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. They include dietary supplements, herbal medicines, and probiotics. While the term “nutraceutical” (“nutrition” and “pharmaceutical”) is relatively recent, the concept dates back hundreds or even thousands of years.
Nutraceuticals are gaining popularity worldwide due to their organic origins and lower side effects compared to conventional synthetic drugs. However, a growing body of literature suggests that when taken out of context (without a prescription) or when consumed at higher dosages or in specific populations, bioactive nutraceuticals may pose medical challenges. This necessitates a scientifically sound understanding of the pros and cons 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 stems from their potential to address chronic diseases, such as cardiovascular disorders, neurodegenerative conditions, and metabolic syndromes, which are often linked to oxidative stress and inflammation.”
The positive benefits of nutraceuticals are well documented. Unfortunately, given their relative novelty, the literature remains relatively scarce on the long-term effects of nutraceuticals, particularly their toxicity upon prolonged use, bioavailability, and interactions with conventional medical interventions. The review also emphasizes the lack of globally harmonized regulatory frameworks governing nutraceutical purity, labeling, and safety claims.
About the Review
The present review aims to collate and summarize existing scientific knowledge on nutraceuticals to elucidate two main topics: the mechanisms determining the therapeutic and toxicological effects of nutraceuticals and recommendations for the safe and effective use of these supplements. The review aims to guide clinicians, policymakers, researchers, and consumers in determining when and how to use nutraceuticals effectively, thereby maximizing their benefits while minimizing potential drawbacks.
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 scientific repositories (Scopus, PubMed, and Web of Science) using a custom keyword search. Title, abstract, and full-text screening shortlisted ~120 publications for inclusion, ensuring only studies exhibiting clinical relevance, methodological rigor, and mechanistic insights were included.
Resveratrol
RSV is gaining increasing scientific interest due to its wide-ranging therapeutic benefits, including cardiovascular, metabolic, neurological, pro-apoptotic, and anti-inflammatory. The bioactive notably reduces oxidative stress, improves lipid metabolism, and reduces blood pressure. It has even been clinically validated to enhance cognitive function and delay Alzheimer’s disease (AD) progression. However, RSV exhibits hormetic effects—protective at low doses but harmful at high doses—with studies demonstrating toxicity at elevated concentrations, including renal impairment and thyroid dysfunction. Chronobiological differences in RSV administration have also been observed, with some evidence suggesting time-of-day may influence lipid peroxidation and drug metabolism.
Curcumin
CUR is arguably the best-studied antioxidant and anti-inflammatory in this review, routinely used to manage diabetes, arthritis, and cardiovascular diseases (CVDs). It also targets several oncological pathways and exhibits significant neuroprotective benefits. CUR’s interference with CVD drugs (e.g., amlodipine) occurs via modulation of CYP3A4 and P-glycoprotein (P-gp) pathways, underscoring the importance of complete health profile assessments before its use. Emerging evidence also notes potential impacts on thyroid hormone levels and reproductive function in animal models, particularly at high doses or via nanoparticle delivery systems.
Piperine
PPR is often used as an adjunct and adjuvant, known for its anti-inflammatory, anti-oxidative stress, neuroprotective, and bioavailability-enhancing properties. Preclinical studies report reproductive toxicity in rats at doses exceeding 10 mg/kg, alongside risks of enhancing side effects of drugs like carbamazepine and warfarin. Emerging evidence also links prolonged high-dose PPR to impaired cognitive performance in animal models, highlighting the importance of understanding and educating the target patient before its prolonged consumption. Recent data also indicate tissue-level alterations and potential organ-specific toxicity in rodent models receiving higher doses.
“A hallmark of PPR is its ability to augment the bioavailability of drugs and nutrients. By inhibiting drug-metabolizing enzymes (e.g., cytochrome P450, UDP-glucuronosyltransferase) and enhancing intestinal absorption, PPR significantly inhibits P-glycoprotein (P-gp). It enhances the efficacy of co-administered compounds, such as CUR and RSV, positioning it as a critical adjunct in nutraceutical formulations.”
Quercetin
QUE is often obtained naturally, derived from the consumption of onions and apples. Its hallmark effects include free radical neutralization, oxidative stress mitigation, and enhancement of cellular integrity, making it a nutraceutical hailed as a potential treatment for cancer, cardiovascular disease (CVD), and aging. While QUE synergizes with certain chemotherapeutics (e.g., methotrexate) to enhance anti-inflammatory effects, it may also interfere with drugs like cyclosporine. High-dose QUE supplements have been linked to pro-oxidant activity and organ damage in preclinical studies. The aglycone form found in supplements exhibits greater bioavailability but also a higher likelihood of interacting with drug-metabolizing enzymes and transporters.
Summary and Future Directions
This review provides extensive details on the pros and cons of four of the most popular available nutraceuticals, highlighting their therapeutic and pharmacological benefits while cautioning against potential dose- and interaction-dependent side effects.
It further suggests emerging technologies, such as nanoencapsulation, to improve targeted delivery and bioavailability of these nutraceuticals, reducing off-target toxicity and ensuring that these bioactives reach their target organs or tissues, thereby maximizing their benefits and mitigating their costs. Additional innovations discussed include in silico molecular docking to predict drug-target interactions, nutrigenomic tools for personalizing interventions, and the Nutraceutical Interaction Risk Score (NIRS) to stratify patients by potential toxicity.
“…while nutraceuticals represent a valuable tool in promoting health and preventing disease, their full potential can only be realized through rigorous scientific research, personalized dosing strategies, and a comprehensive understanding of both their benefits and potential risks. The investigational integration of nanotechnology and smart materials has emerged as a transformative approach to enhance the efficacy and safety of nutraceuticals.”
