Stilbenoid

Other Names

1,2-Diphenylethylene derivativesC6-C2-C6 phenolicscis-StilbenoidsHydroxylated derivatives of stilbeneHydroxystilbenesMonomeric stilbenoidsNatural stilbenesOligomeric stilbenoidsOligostilbenoidsPhenylpropanoid-derived stilbenesPhytoalexins (stilbene-type)Plant phenolic stilbenesPlant stilbenesResveratrol-class compoundsStilbene derivativesStilbene glucosidesStilbene phenolicsStilbene phytoalexinsStilbene polyketidesStilbene secondary metabolitesStilbene-class polyphenolsStilbene-type polyphenolsStilbenoid phenolicsStilbenoidstrans-Stilbenoids

Synopsis

Stilbenoids: A Comprehensive Reference

1. Identity: Chemical Classification, Natural Sources, and Common Preparations

1.1 Taxonomy and Chemical Identity

Stilbenoids are a family of polyphenols known for the complexity of their structure and for their diverse biological activities, occurring with a limited but heterogeneous distribution in the plant kingdom. The monomeric stilbene (trans-1,2-diphenylethylene) aglycone structure consists of two phenyl rings joined by an ethylene bridge. Stilbenes may exist as the cis- or trans-isomer, but the trans-isomer is the more common and stable configuration. They share a common backbone stilbene structure but differ in the type and position of substituents on the ring.

More than 300 representatives of stilbenoids are known — a group of natural, synthetic, and semi-synthetic biologically active substances that, according to their chemical structure, belong to the group of polyphenolic compounds known as phenylpropanoids. A broader count is reported in some comprehensive analyses: a total of 459 natural stilbene compounds from 45 plant families and 196 plant species have been identified.

Based on their chemical structure, stilbenoids can be classified into five major groups: simple stilbenes, prenylated and geranylated stilbenes, 2-phenyl-benzofuran derivatives, carbon-substituted stilbenes that do not belong to the prenylated and geranylated stilbenes group, and various other structures. Stilbenoids exist as monomers or oligomers. They may also be found free (aglycone) or conjugated as glucosides. For example, piceid is resveratrol-3-O-glucoside.

1.2 Key Individual Stilbenoid Compounds

The class encompasses numerous structurally related molecules. The most thoroughly studied and supplemented include:

Resveratrol (trans-3,5,4′-trihydroxystilbene): Resveratrol is a trihydroxy stilbene derivative (3,5,4′-trihydroxystilbene) found in grapes, berries, peanuts, and red wine. It is an antimicrobial and antioxidative compound (phytoalexin) with pleiotropic properties, naturally produced by plants and stored in many dietary sources like nuts, grapes, apples, red fruits, black olives, capers, red rice, as well as red wines.
Pterostilbene (3,5-dimethoxy-4′-hydroxy-trans-stilbene): Pterostilbene is the dimethylether analog of resveratrol, where methylated polyphenol analogs may overcome limitations to pharmacologic efficacy relative to resveratrol. Pterostilbene is a naturally occurring compound found in plants such as blueberries (Vaccinium) and Chinese dragon's blood.
Piceatannol (3,4,3′,5-tetrahydroxystilbene): Piceatannol, a hydroxylated derivative from resveratrol, exerts various biological activities ranging from cancer prevention, cardioprotection, neuroprotection, anti-diabetic properties, and depigmentation.
Pinosylvin: Pinosylvin is suggested as a functional compound responsible as a defense mechanism against pathogens and insects for a wide range of plants, especially pines.
Piceid (polydatin): The glycosylated form of resveratrol, piceid or resveratrol-3-O-glucoside, represents a common naturally occurring conjugate.
Gnetol: Gnetol is another stilbenoid whose biological effects have been investigated alongside resveratrol, pterostilbene, and piceatannol.

The most important stilbenoid phytoalexins include astringin, resveratrol, pinosylvin, piceid, piceatannol, and pterostilbene, even though hundreds of stilbenoids occur naturally via different chemical reactions.

1.3 Botanical Sources and Plant Distribution

Stilbenes have been isolated from Bryophytes (Marchantiales order), Monilophytes (Ophioglossales and Polypodiales orders), gymnosperms (Gnetales and Pinales orders), and angiosperms (Magnoliophyta division, in both Monocots and Eudicots).

The most prominent stilbene-containing plant family, the Vitaceae, represented by the famous wine-producing grape vines Vitis vinifera L., is one of the richest sources of novel stilbenes currently known, together with other families such as Dipterocarpaceae, Gnetaceae, and Fabaceae. Over 60 stilbenoids can be found in Vitis vinifera as monomers, such as trans-resveratrol or piceatannol, and as oligomers, which are usually in their trans configuration.

Resveratrol was originally isolated by Takaoka from the roots of white hellebore in 1940, and later, in 1963, from the roots of Japanese knotweed. Japanese knotweed (Polygonum cuspidatum) is a perennial species with spreading rhizomes and numerous reddish-brown, freely branched stems. Its root is much richer in resveratrol than any other known plant and is now the primary natural source of resveratrol.

Food sources of stilbenoids include: The main food sources are the fruits of grapes, blueberries, peanuts, and cocoa. More than 300 representatives of stilbenoids are known as a group of natural, synthetic, and semi-synthetic biologically active substances.

1.4 Biosynthesis in Plants

Stilbenoids are classified as phytoalexins, which are antimicrobial compounds produced de novo in plants to protect against fungal infection and toxins. Stilbenes are synthesized in plants via the phenylpropanoid pathway in a similar fashion to flavonoids. The biosynthetic pathway begins with the conversion of phenylalanine to cinnamate by the action of phenylalanine ammonia lyase. Stilbenes are phytoalexins synthesized by plants in response to viral, fungal, and bacterial attacks. Biosynthesis of stilbenes in plants involves the combination of one CoA-ester of a cinnamic acid derivative and three malonyl-CoAs. The resulting polyketide is then used to produce either stilbenoids or flavonoids based on whether stilbene synthase (STS) or chalcone synthase is involved in the process.

1.5 Common Commercial Forms and Preparations

In commercial dietary supplement use, stilbenoids — principally resveratrol — appear in several forms:

Standard capsules/tablets: Resveratrol is currently mainly used as an antioxidant dietary supplement to protect against cardiovascular problems and some alterations associated with aging, and as a supplement in treatment of cancer, obesity, diabetes, or hypercholesterolemia. The doses of resveratrol used in these supplements range from 50 to 500 mg per capsule.
Micronized formulations: Micronized formulations (e.g., SRT501) reduce particle size to less than 5 micrometers, resulting in a 3- to 4-fold increase in plasma concentration and area under the curve (AUC) compared to unprocessed resveratrol.
Nanoformulations and lipid carriers: To overcome bioavailability limitations, various strategies have been implemented, which involve modifying the administration routes and formulations, including cocrystals, prodrugs, nanoparticles, lipid-based encapsulation, and beads.
Plant-extract standardized products: Polygonum cuspidatum root extract is a dominant commercial source. One clinical study used an oral extract of P. cuspidatum 200 mg containing resveratrol 40 mg over 6 weeks for anti-inflammatory effect.
Topical preparations: Antioxidant-rich stilbene compounds are also incorporated via topical applications like skincare and sunscreen products.

2. Traditional and Historical Use

2.1 Traditional Chinese Medicine

Polygonum cuspidatum has been used in traditional Japanese and Chinese medicine to treat a wide range of afflictions, including fungal diseases, various skin inflammations, cardiovascular and liver diseases. In traditional Chinese medicine, Japanese knotweed is known as "Hu Zhang" and has been used for centuries for various purposes.

Huzhang (Japanese Knotweed) has been used in traditional Chinese medicine as well as in Japan and Korea for many years. Although used for various applications, few clinical studies validate claims, and guidance regarding dosing or safety is limited.

2.2 Phytoalexin Discovery and Historical Identification

The history of stilbenoid detection is associated with the discovery of the protective functions of plants in response to the action of external stimuli. Further study revealed pronounced antioxidant properties. Resveratrol's identification as a discrete chemical entity dates to 1940: resveratrol was originally isolated by Takaoka from the roots of white hellebore in 1940, and later, in 1963, from the roots of Japanese knotweed.

Scientific attention to resveratrol dramatically accelerated in the 1990s when researchers began investigating the "French Paradox" — observations linking moderate red wine consumption to lower rates of cardiovascular disease in French populations. Resveratrol and other related compounds are heterogeneously distributed in plants and are mainly found in grapes and wine.

2.3 Traditional Preparations

In East Asian traditions, the primary vehicles for stilbenoid-containing plants were decoctions and powdered preparations of roots and rhizomes. Clinical evidence on which to base dosing guidelines is limited. One clinical study used an oral extract of P. cuspidatum 200 mg containing resveratrol 40 mg over 6 weeks for anti-inflammatory effect, reflecting modern efforts to quantify what traditional practitioners administered empirically. Dietary intake through fermented grape products (wine) represents another culturally embedded route of stilbenoid exposure documented across Mediterranean and Asian cultures.

3. Key Constituents, Active Compounds, and Mechanisms of Action

3.1 Structural Basis of Bioactivity

The diversity and the simplicity of stilbenes' chemical structures together with the numerous biological sources are key elements that can simplify both the isolation of these compounds and the drug design of novel bioactive molecules. Natural stilbenes have been shown to possess a wide range of biological activities, such as antioxidant, anti-inflammatory, antihyperglycemic, cardioprotective, neuroprotective, and antineoplastic properties.

3.2 SIRT1 Activation and the Sirtuin Pathway

Resveratrol is a polyphenol extracted from grape skins, red wine, and other edible materials, and is probably the most relevant SIRT1-activating natural product. This stilbenoid derivative has exerted cardioprotective activities by means of SIRT1 activation in various in vitro and in vivo models of myocardial ischemia/reperfusion injury, and it has been demonstrated to increase lifespan in Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster.

Resveratrol acts as a pan-SIRT activator, though its precise SIRT1 activation mechanism — direct or via NAD+ modulation — remains debated. In obesity, resveratrol promotes adipose beiging and thermogenesis, yet clinical weight loss is modest. The most studied member of the sirtuin enzyme class is SIRT1, whose expression is associated with increasing insulin sensitivity. SIRT1 has been implicated in both tumorigenic and anticancer processes, and is reported to regulate essential metabolic pathways, suggesting that its activation might be beneficial against disorders of the metabolism. Via regulation of p53 deacetylation and modulation of autophagy, SIRT1 is implicated in cellular response to caloric restriction and lifespan extension.

3.3 NF-κB Inhibition and Anti-Inflammatory Pathways

Resveratrol and other natural stilbenoids, including piceatannol, pterostilbene, and gnetol, are well-known anti-inflammatory compounds with indisputable activity in vitro as well as in vivo. Their molecular targets include inducible nitric oxide synthase, cyclooxygenases, leukotrienes, nuclear factor kappa B (NF-κB), tumor necrosis factor α (TNF-α), interleukins, and many more. This anti-inflammatory activity together with their antioxidant activity is believed to underlie their other positive health effects against cancer, cardiovascular and neurodegenerative diseases, or diabetes.

3.4 AMPK Activation and Metabolic Regulation

Resveratrol modulates several key signaling pathways including NF-κB, SIRT1, AMPK, MAPK, Nrf2, and PI3K/AKT/mTOR. It reduces oxidative stress, inhibits inflammatory cytokines, regulates apoptosis, improves mitochondrial performance, and activates endogenous antioxidant systems. The primary pharmacological impacts focus on the AMPK/SIRT1/PGC-1α axis, PI3K/AKT pathways, and epigenetic modulations.

3.5 Antioxidant Mechanisms

Mechanistically, resveratrol is known to modulate critical signaling pathways such as the activation of sirtuin 1. These actions collectively contribute to the attenuation of oxidative stress, regulation of apoptosis, and promotion of autophagy. Stilbenoids act as direct free-radical scavengers as well as indirect antioxidants through upregulation of endogenous antioxidant defense systems including the Nrf2 pathway.

3.6 Bioavailability Constraints — A Mechanistic Limitation

Resveratrol is characterized by poor bioavailability, which is mainly caused by an extensive in vivo conversion into its sulfate and gluconate metabolites. The use of resveratrol is limited by its being easily oxidizable and extremely photosensitive. In addition, its low solubility in water and its rapid metabolism in enterocytes and hepatocytes (where sulphate and glucuronic conjugates are produced), as well as its rapid elimination, make the oral resveratrol bioavailability very low.

Pterostilbene shows markedly superior pharmacokinetics: Pterostilbene has a longer half-life (105 minutes versus 14 minutes) and higher oral bioavailability (80% versus 20%) compared to resveratrol. Pterostilbene also has low total body clearance and subsequent Vss, which suggests extensive tissue distribution. The two methoxy groups cause pterostilbene to be more lipophilic, which increases oral absorption and gives pterostilbene a higher potential for cellular uptake.

In vitro studies aimed at identifying cellular targets are conducted at concentrations ranging from nM to µM, which challenge the translatability of data. After ingestion, these compounds are detected as phase II metabolites and their blood level does not exceed concentrations in the nM range. Substantial amounts of the compounds and their metabolites are degraded in the colon by intestinal microbiota, giving rise to small phenolic acids and aromatic catabolites which are absorbed by the circulatory system.

3.7 Antiviral Mechanisms

Stilbenoids are effective against different DNA and RNA viruses; the relevant mechanisms comprise reduction in viral replication, inhibition of viral genome expression, and viral attachment to cells.

4. Scientific Evidence by Area of Health Use

4.1 Cardiovascular Health

Evidence overview: This is one of the most studied areas for stilbenoids.

Many studies of resveratrol have focused on its favorable effects on pathological conditions related to cardiovascular diseases and their risk factors. The aim of extensive review work has been to summarize the wide beneficial effects of resveratrol on the cardiovascular system, including signal transduction pathways of cell longevity, energy metabolism of cardiomyocytes or cardiac remodeling, and its anti-inflammatory and antioxidant properties.

The results from experimental studies suggest that resveratrol exerts cardioprotective effects through the modulation of various antioxidant, anti-inflammatory, and anti-hypertensive pathways, and microbiota composition. However, results in humans are conflicting, possibly due to interindividual different responses. The gut microbiota, a complex microbial community that inhabits the gastrointestinal tract, has been called out as potentially responsible for modulating the biological activities of phenolic metabolites in humans.

Over the last 20 years, there have been almost 200 studies evaluating resveratrol across at least 24 indications, including cancer, menopause symptoms, diabetes, metabolic syndrome, and cardiovascular disease. Despite this volume, resveratrol has long been proposed as being beneficial to human health across multiple morbidities, yet there is currently no conclusive clinical evidence to advocate its recommendation in any healthcare setting. A large cohort with high-quality clinical data and clearly defined biomarkers or endpoints are required to draw meaningful conclusions.

Evidence strength: Preclinical data are robust; human clinical trial data are mixed, limited by small sample sizes, varying doses, and inconsistent endpoints.

4.2 Cancer Prevention and Oncology

Evidence overview: Stilbenoids have been extensively studied in preclinical cancer models across multiple tumor types.

Resveratrol has been shown to be an effective chemopreventive agent in multiple murine models of human cancers. It has the capacity to interact with multiple molecular targets and appears to be relatively non-toxic at least at the doses tested in these models. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers.

In terms of human clinical evidence, most of the clinical trials of resveratrol have focused on cancer, neurological disorders, cardiovascular diseases, diabetes, non-alcoholic fatty liver disease (NAFLD), and obesity. For neurological disorders, cardiovascular diseases, and diabetes, the current clinical trials show that resveratrol was well tolerated and beneficially influenced disease biomarkers. However, despite an abundance of laboratory and animal research, there is little clinical evidence that resveratrol is an effective therapeutic in humans.

Preclinical evidence for piceatannol in cancer: Piceatannol has been shown in preclinical studies to have the ability to inhibit or reduce the growth of cancers in various organs such as the brain, breast, lung, colon, cervical, liver, prostate, and skin.

One important safety signal emerged from oncological use: a study of a high-dose micronized formula in multiple myeloma patients was stopped due to serious adverse events that included renal failure.

Evidence strength: Preclinical (in vitro and animal) evidence is extensive; human clinical evidence for cancer treatment/prevention is currently insufficient to support clinical recommendations.

4.3 Neuroprotection and Alzheimer's Disease

Evidence overview: This is an area of active clinical investigation.

Preclinical studies have provided strong evidence that stilbenes can regulate many cellular pathways implicated in neurodegeneration, with resveratrol being a well-studied compound that has shown the ability to reduce oxidative damage, promote neurogenesis, and enhance mitochondrial function — crucial for maintaining brain health. In preclinical animal models, initial research has also shown promise in additional substances such as piceatannol and pterostilbene.

A significant human trial in Alzheimer's disease has been conducted: 119 subjects were enrolled in a phase 2 randomized, double-blind, placebo-controlled trial of resveratrol in subjects with mild-to-moderate AD, with dosage stepped up to 2 g pure, synthetic resveratrol by mouth daily, for 12 months. Key findings: compared to placebo, resveratrol stabilizes the progressive decline in CSF Aβ40 and plasma Aβ40 levels as dementia advances. In individuals with biomarker-confirmed AD at baseline, resveratrol also stabilizes CSF Aβ42 levels. Specifically, markers of neuronal damage, including neuron-specific enolase and hyperphosphorylated neurofilaments, were reduced. Microglial activation was measured via TREM-2 at baseline and after resveratrol treatment. Resveratrol significantly reduced CSF TREM2 levels and decreased inflammation and tissue damage, including matrix metalloprotease (MMP)-9.

Mechanistically in neurodegeneration: these results indicate that resveratrol can provide neuroprotection against AD by enhancing the activity of SIRT1. However, despite promising results in preclinical research, the use of stilbenes in clinical trials is currently limited, with most studies focusing on resveratrol. Although several clinical studies have demonstrated the beneficial impact of resveratrol supplementation on brain health, other investigations have yielded ambiguous findings, underscoring the urgent need for more comprehensive and precisely planned clinical investigations.

For piceatannol in Alzheimer's specifically: piceatannol is the only resveratrol analogue that reduces Aβ levels without cytotoxicity in the cell-based models studied, though this remains preclinical evidence.

Evidence strength: Mechanistic and preclinical evidence is strong; the phase 2 AD trial produced interesting CSF biomarker data but was underpowered for clinical outcomes. Definitive clinical evidence is lacking.

4.4 Diabetes and Metabolic Syndrome

Evidence overview: Multiple clinical trials have examined stilbenoids — especially resveratrol — in type 2 diabetes and metabolic syndrome.

For diabetes, the current clinical trials show that resveratrol was well tolerated and beneficially influenced disease biomarkers. It has been established that the RSV-SIRT axis represses oxidative stress-induced hyperglycemia and cytokine toxicity via deacetylating FOXO1 and the NF-κB subunit p65 on β-cells.

For piceatannol, piceatannol is a known AMPK activator and has shown its effect on suppressing rises in blood glucose levels at early stages and improving impaired glucose tolerance at late stages in mice.

Despite robust preclinical data, a significant translational gap exists. Clinical evidence is heterogeneous, often contradicting animal studies due to varying dosages, durations, and population characteristics.

Evidence strength: Mixed clinical evidence; preclinical data are promising but human trial results are inconsistent across studies.

4.5 Lipid Metabolism and Hypercholesterolemia (Pterostilbene)

Evidence overview: Pterostilbene has been specifically evaluated in human trials for cardiometabolic parameters.

A prospective, randomized, double-blind placebo-controlled intervention trial enrolled patients with hypercholesterolemia (defined as a baseline total cholesterol ≥200 mg/dL and/or baseline LDL cholesterol ≥100 mg/dL). Eighty subjects were divided equally into one of four groups: pterostilbene 125 mg twice daily, pterostilbene 50 mg twice daily, pterostilbene 50 mg + grape extract (GE) 100 mg twice daily, and matching placebo twice daily for 6–8 weeks. Animal studies have demonstrated efficacy in cardiometabolics (e.g., cholesterol and blood glucose), as well as cancer and cognition mediators.

Findings including LDL increases and blood pressure reduction may indicate cross-selectivity for PPAR-γ activation with pterostilbene in certain patients.

Evidence strength: Preliminary human data; the primary human trial examined safety parameters rather than efficacy endpoints as primary outcomes. Larger, adequately powered trials for lipid endpoints are needed.

4.6 Anti-Inflammatory Effects

There is a rigorous debate about the real effect of these compounds on human health. It is argued that the concentration of stilbenoids in food and beverages is too low to have any therapeutic potential, and this concentration is further reduced by their low bioavailability and extensive metabolism.

One clinical study directly assessed anti-inflammatory effects: one clinical study used an oral extract of P. cuspidatum 200 mg containing resveratrol 40 mg over 6 weeks for anti-inflammatory effect.

Evidence strength: Anti-inflammatory mechanisms are well-characterized in vitro and in vivo; clinical translation and dose relevance remain uncertain.

4.7 Skin Photoaging

A scoping review presents an overview of the evidence on the effects of pterostilbene and resveratrol on skin photoaging. The findings suggest that resveratrol significantly improves skin photoaging, while preliminary evidence indicates that pterostilbene may offer advantages over resveratrol. However, due to the limited research on pterostilbene, further studies are required to confirm its efficacy.

Evidence strength: Preliminary; only 9 eligible articles were found by this scoping review, indicating a sparse evidence base in humans.

4.8 Antiviral Activity

Within the huge class of plant secondary metabolites, resveratrol-derived stilbenoids present a wide structural diversity and mediate a great number of biological responses relevant for human health. The antiviral activity of resveratrol has been extensively studied, though little is known about the efficacy of its monomeric and oligomeric derivatives. Stilbenoids are effective against different DNA and RNA viruses; the relevant mechanisms comprise reduction in viral replication, inhibition of viral genome expression, and viral attachment to cells.

Evidence strength: Largely in vitro and animal data; clinical antiviral efficacy has not been established in adequately powered human trials.

5. Body Systems and Health Areas Associated with Stilbenoids

Stilbenoids exert various biological activities ranging from cardioprotection, neuroprotection, anti-diabetic properties, depigmentation, anti-inflammation, cancer prevention and treatment. Pharmacological studies also show that stilbenes have various activities such as anticancer, antimicrobial, antioxidant, anti-inflammatory, anti-degenerative disease, anti-diabetic, neuroprotective, anti-aging, and cardioprotective effects.

Cardiovascular system: Modulation of platelet aggregation, endothelial function, vascular inflammation, lipid profiles, and myocardial protection.
Central nervous system: Neuroprotection, reduction of amyloid-beta accumulation, neuroinflammation modulation, and SIRT1-mediated pathways.
Metabolic system: Glycemic regulation, insulin sensitivity, AMPK activation, lipid metabolism, and adipose tissue function.
Immune system: Resveratrol beneficially alters gut microbiota composition and microbial metabolites, contributing to improved metabolic homeostasis.
Integumentary system (skin): Antioxidant photoprotection, anti-melanogenic effects, and anti-aging actions through topical and oral routes.
Oncological applications: Preclinical activity across multiple cancer types through anti-proliferative, pro-apoptotic, and anti-angiogenic mechanisms.
Antiviral defense: Broad-spectrum in vitro and animal antiviral activity.

6. Dosage Forms and Dosages Reported in Studies

The following dosages are drawn directly from published clinical study reports:

Alzheimer's disease trial (phase 2, 52-week): Dosage stepped up to 2 g pure, synthetic resveratrol by mouth daily, for 12 months.
Cognitive and cerebrovascular studies: Healthy adults randomly received a single dose of either 150 mg, 75 mg, or 150 mg of Veri-Sperse resveratrol. The majority of clinical studies have been conducted administering 150 mg/day of resveratrol.
Cognitive performance dose-finding: A study in thirty-six adults (40–80 years of age) were randomized to consume single doses of resveratrol (0, 75, 150, and 300 mg), and 75 mg showed the best efficacy for blood flow velocity measured during a cognitive battery of tests.
Pterostilbene — lipid/safety trial: Groups received pterostilbene 125 mg twice daily, pterostilbene 50 mg twice daily, pterostilbene 50 mg + grape extract (GE) 100 mg twice daily, or matching placebo twice daily for 6–8 weeks.
Pterostilbene — miRNA expression pilot: This pilot study investigated the safety of continuous intake at doses of 10 or 100 mg/day over 12 weeks. A double-blind, placebo-controlled parallel-arm comparison trial was conducted with 30 healthy men.
Polygonum cuspidatum extract anti-inflammatory study: An oral extract of P. cuspidatum 200 mg containing resveratrol 40 mg was administered over 6 weeks.
Phase I study in colorectal cancer liver metastases: Six patients received 5 grams per day of resveratrol for a total of 14 days. Resveratrol was well tolerated in general, with the most common adverse effects being mild nausea and diarrhea.
Upper tolerated dose: Human clinical trials have shown resveratrol to generally be safe and well tolerated at doses of up to 5 g, though dose-related gastrointestinal upset has been reported.
Commercial supplement range: Doses of resveratrol used in dietary supplements range from 50 to 500 mg per capsule.

7. Safety Considerations and Drug Interactions

7.1 General Tolerability

Side effects may include minor gastrointestinal upset, nausea, headache, and fatigue, and possible supplement-drug interactions with estrogens and anticoagulants. There have been multiple trials of resveratrol in human subjects, but the dose regimen and duration of therapy has varied greatly, and many trials lacked information on adverse events, ALT elevations, and hepatotoxicity. Nevertheless, in most studies there was no mention of serum ALT elevations or only rare and mild-to-moderate increases that were asymptomatic and resolved rapidly upon stopping therapy.

In general, resveratrol is a well-tolerated compound with a robust safety profile. No adverse effects related to resveratrol were reported in clinical studies evaluating doses up to 1 gram of resveratrol per day. Resveratrol is well tolerated even at higher doses; however, there is an increase in gastrointestinal side effects at doses exceeding 1 gram per day.

7.2 Gastrointestinal Effects at High Doses

Whereas resveratrol appears to be well tolerated in some studies, high doses can cause gastrointestinal side effects such as diarrhea. Mild to moderate gastrointestinal symptoms and diarrhea at high doses (2.5 and 5 g daily) have been reported.

7.3 Renal Safety Signal at High Doses

A study of a high-dose micronized formula (SRT501) in multiple myeloma patients was stopped due to serious adverse events that included renal failure. This finding is specific to the high-dose micronized formulation context and does not represent a general finding across all resveratrol administration.

7.4 Anticoagulant and Antiplatelet Interactions

Although clinical relevance is yet to be determined, resveratrol inhibits platelet aggregation in vitro, so concurrent use with antiplatelet drugs may increase bleeding risk. Therefore, use of this supplement should be discussed with the treating physician.

7.5 Estrogenic and Hormonal Activity

Resveratrol exhibits estrogen-like properties and activates transcription by both estrogen and androgen receptors, which can lead to the stimulation of cancer cell proliferation. Patients with hormone-sensitive cancers should use caution as resveratrol at concentrations between 3 and 10 μM exhibits estrogen-like properties and activates transcription by both estrogen and androgen receptors that may lead to the stimulation of cancer cell proliferation.

7.6 CYP450 Enzyme Inhibition and Drug Metabolism

Resveratrol inhibits CYP450 enzymes and may increase the risk of adverse effects of certain drugs. This has potential clinical relevance for drugs with narrow therapeutic indices that are metabolized by these enzymes. Of the few relevant clinical trials that mention drug interactions, resveratrol has been reported to inhibit the phase I drug metabolism enzyme CYP3A4.

7.7 Pterostilbene Safety

Pterostilbene is generally safe for use in humans up to 250 mg/day. In the randomized controlled pterostilbene safety trial, there were no adverse drug reactions (ADRs) on hepatic, renal, or glucose markers based on biochemical analysis. The potential effects of many drug interactions with pterostilbene remain unclear. The mode of administration of pterostilbene seems to play an important role in its bioavailability, as the administration of intravenous doses shows a higher distribution when compared to oral intake.

7.8 General Evidence Limitations for Safety

The results presented cover a myriad of models, from cell culture to animal studies as well as clinical human trials. Although positive results were obtained in most cell culture and animal studies, further human studies are needed to substantiate beneficial effects of stilbenoids. The toxicity of stilbenoids has been reviewed in recent papers, and, in most cases, the effective concentrations applied are well below the toxicity limit.

References

Health Conditions

Health conditions that Stilbenoid may help support.

No conditions available.

Body Systems

Body systems that Stilbenoid may help support.

No body systems available.