Polidatina

Otros Nombres

(E)-Piceid(E)-Polydatin3,4′,5-Trihydroxystilbene-3-β-D-glucopyranoside3,4′,5-Trihydroxystilbene-3-β-D-glucoside3,4′,5-Trihydroxystilbene-3-β-monoglucoside3,5,4′-trihydroxystilbene 3-glucoside3,5,4′-Trihydroxystilbene-3-O-β-D-glucopyranoside3-(β-D-Glucopyranosyloxy)-5-[(E)-2-(4-hydroxyphenyl)vinyl]phenol3-Hydroxy-5-[(E)-2-(4-hydroxyphenyl)ethenyl]phenyl-β-D-glucopyranoside3-Hydroxy-5-[2-(4-hydroxyphenyl)ethenyl]phenyl-β-D-glucoside3-O-β-D-resveratrol-glucopyranoside4′,5-Dihydroxystilben-3-yl β-D-glucopyranoside4′,5-Dihydroxystilbene-3-O-β-D-glucosidecis-PolydatinE-Resveratrol 3-O-glucopyranosidePiceidPieceidPolydatineResveratrol 3-beta-mono-D-glucosideResveratrol 3-glucosideResveratrol 3-O-glucosideResveratrol glucosideResveratrol-3-O-β-D-glucopyranosideResveratrol-3-O-β-mono-D-glucosideResveratrol-3-β-D-glucopyranosideResveratrol-3-β-mono-D-glucosidetrans-Piceidtrans-Polydatintrans-Resveratrol 3-O-beta-D-glucosidetrans-Resveratrol-3-O-β-D-glucopyranosidetrans-Resveratrol-3-O-β-D-Glucosidetrans-Resveratrol-O-β-glucosideβ-D-Glucopyranoside, 3-hydroxy-5-[2-(4-hydroxyphenyl)ethenyl]phenyl

Sinopsis

Polydatin (Piceid): A Comprehensive Encyclopedic Reference

1. Identity: Chemical Names, Botanical Source, and Forms

1.1 Nomenclature and Chemical Identity

Polydatin (also named piceid, (E)-piceid, (E)-polydatin, trans-polydatin; systematic name: 3,4′,5-trihydroxystilbene-3-β-d-glucoside) is a monocrystalline compound originally isolated from the root and rhizome of Polygonum cuspidatum Sieb. et Zucc. Polydatin (PD), also known as piceid, is a monocrystalline substance and a member of the stilbene family. It is a derivative of the phytoalexin resveratrol (3,4′,5-trihydroxystilbene), where the hydroxyl group at position C-3 is replaced by a glucoside group. More precisely, polydatin (PLD) is the 3-O-β-glucopyranoside of the well-known stilbenoid compound resveratrol.

It is a glucoside of resveratrol (3,4′,5-trihydroxystilbene) in which the glucoside group bound to position C-3 substitutes a hydroxyl group, placing it within the stilbene phytoalexin class. The trans-isomers of stilbenes, including PD, are recognized for their higher bioactivity compared to their cis-isomer counterparts. There are four main derivatives of PD in nature, including trans-polydatin, trans-resveratrol, cis-polydatin, and cis-resveratrol.

The biosynthesis of PD involves utilizing the polyketide and phenylpropanoid pathways. The process initiates with phenylalanine ammonia-lyase (PAL), which catalyzes the deamination of phenylalanine to produce cinnamic acid. Cinnamate-4-hydroxylase (C4H) then facilitates the hydroxylation of cinnamic acid, generating p-coumaric acid.

1.2 Primary Botanical Sources

Polydatin is primarily isolated from the rhizome and root of Polygonum cuspidatum, traditionally used against inflammation, infection, jaundice, skin burns, and hyperlipemia. Reynoutria japonica is an invasive plant from the Far East and a main source of polydatin at industrial scale. The plant families Vitaceae, Liliaceae, and Leguminosae are also prominent sources of polydatin extraction.

Polydatin is also detected in grape, peanut, hop cones, red wines, hop pellets, cocoa-containing products, chocolate products, and many daily diets. The most common dietary sources of polydatin are grape juice and red/white wines. Cis-polydatin is the predominant isoform in carbonated wines and rosé, while the trans isomer is abundant in berries, peanuts, grapes, and pistachios.

As one of the most abundant forms of resveratrol in nature, polydatin is the major bioactive compound of Polygonum cuspidatum root, which is used to treat cardiac ailments, including atherosclerosis and inflammation, in Japanese and Chinese folk medicine.

1.3 Common Forms and Preparations

Polydatin is commercially available in several forms for research and dietary supplement use. Resveratrol, polydatin, quercetin, emodin, and their derivatives are the primary active phytochemical components of P. cuspidatum. Standardized root extracts are the most common form. Production methods include direct extraction from plant material or biotransformation via microbial glucosylation of resveratrol using bacteria such as Bacillus cereus. For clinical investigations, polydatin has been used both as a standalone oral formulation and, most frequently in human trials, as a co-micronized combination with palmitoylethanolamide (PEA). Although resveratrol has similar beneficial effects, its low bioavailability has remained a problem. Glycosylation increases the solubility of resveratrol in an aqueous environment, thus improving its bioavailability.

2. Traditional and Historical Use

2.1 Traditional Chinese Medicine (TCM)

Polygonum cuspidatum Sieb. et Zucc (Polygonaceae), the root of which is included in the Chinese Pharmacopoeia under the name "Huzhang," has a long history as a medicinal plant and vegetable. Polygonum cuspidatum has been used in traditional Chinese medicine for the treatment of inflammation, hyperlipemia, and related conditions. PC has been prescribed for medicinal purposes for thousands of years in China.

This is a traditional Chinese medicine that has long been used in China as an analgesic, anti-pyretic, diuretic, and expectorant. It is a glucoside of resveratrol (3,4′,5-trihydroxystilbene) in which the glucoside group bound to the position C-3 substitutes a hydroxyl group.

Huzhang has the effects of clearing heat and detoxifying, promoting dampness and eliminating jaundice, dispersing blood stasis and relieving pain, resolving phlegm and relieving cough, and is often used to treat arthritis, hepatitis, jaundice, hyperlipidemia, and cough.

In China, Hu Zhang is usually used in combination with other TCM herbs. The therapeutic uses of those Hu Zhang-containing TCM prescriptions or formulations are for treating cough, hepatitis, jaundice, amenorrhea, leucorrhea, arthralgia, burns, and snake bites.

2.2 Japanese and Korean Traditional Use

The plant (Japanese knotweed) is widely used in traditional Chinese medicine to treat infection, inflammatory diseases, and circulatory problems. Hu Zhang is widely distributed in the world. It can be found in Asia and North America and is used as folk medicine in countries such as Japan and Korea. In Japan, the plant is known as Itadori and has been used in similar folk medicinal contexts as in China.

Polygonum cuspidatum grows in southwest, central, and southern China, and is more common on slopes of hills and ditches at altitudes of 500–2500 meters. Polygonum cuspidatum with a wide spectrum of pharmacological effects has been used for treatment of inflammation, favus, jaundice, scald, and hyperlipemia.

2.3 Preparation Methods in Traditional Use

The dried rhizomes and roots of perennial Polygonum cuspidatum plants can be processed to obtain the traditional Chinese medicine, also named HuZhang in Chinese. Slices of Polygonum cuspidatum, as used in Chinese medicine, are mostly short, cylindrical or irregular and thick, with a length of 1–7 cm and a diameter of 0.5–2.5 cm. Traditional preparations included decoctions of the dried sliced root and rhizome, either alone or in compound formulas with complementary herbs.

3. Key Constituents and Active Compounds

3.1 Phytochemical Context Within the Source Plant

Resveratrol, polydatin, quercetin, emodin, and their derivatives are the primary active phytochemical components of P. cuspidatum. Within this context, polydatin occupies a special position as the glycosylated (and therefore more stable and soluble) form of resveratrol. In plants, resveratrol is present as a glycoside — polydatin — in which a glucoside group bound to the C-3 position substitutes for a hydroxyl group.

3.2 Structural Features Relevant to Activity

In resveratrol there are three hydroxyl groups at positions 3, 4, and 5 of the stilbene scaffold, whereas in polydatin, position 3 is occupied by a glucopyranoside ring. Substitution of position 3 with a sugar molecule does not interfere with the scavenger functions of the hydroxystilbene, which is ascribed in major measure to the 4′ OH.

Polydatin (resveratrol-3-O-β-D-glucoside) is a common water-soluble derivative of resveratrol, and it exhibits anticancer and antioxidant activities. Polydatin is more resistant to enzymatic oxidation than resveratrol. Glycosylation of resveratrol can extend its half-life in the cell and maintain the beneficial antioxidant capacity and biological properties.

4. Mechanisms of Action

4.1 Antioxidant Mechanisms

Polydatin is a natural potent stilbenoid polyphenol and a resveratrol derivative with improved bioavailability. Polydatin possesses potential biological activities predominantly through the modulation of pivotal signaling pathways involved in inflammation, oxidative stress, and apoptosis.

A central antioxidant mechanism involves the Sirt1/Nrf2 axis. It has been reported that polydatin is a potent anti-inflammatory plant secondary metabolite, beneficially promoting miR-200a expression to regulate the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor E2-related factor 2 (Nrf2) antioxidant axis. This pathway, in turn, suppresses nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome activation against diverse chronic inflammation-related diseases in vivo.

Research has found that polydatin significantly reversed the downregulation of Sirt1 in terms of protein expression and deacetylase activity and attenuated fibronectin (FN) and TGF-β1 expression in glomerular mesangial cells exposed to advanced glycation end-products (AGEs). The activation of the Nrf2-ARE pathway by PD eventually led to the quenching of ROS overproduction sharply boosted by AGEs.

According to previous studies, polydatin exerts significantly protective and curative effects on oxidative stress-associated diseases via various molecular mechanisms, including amelioration of liver function and insulin resistance, inhibition of proinflammatory cytokines, lipid accumulation, endoplasmic reticulum stress and autophagy, regulation of PI3K/Akt/mTOR, and activation of hepatic stellate cells (HSCs), as well as increase of antioxidant enzymes (such as catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), superoxide dismutase (SOD), glutathione reductase (GR), and heme oxygenase-1 (HO-1)).

4.2 Anti-inflammatory Mechanisms

One key anti-inflammatory response is mainly orchestrated by extracellular-signal-regulated kinases (ERK1/2), c-Jun N-terminal kinase 1/2 (JNK1/2), and p38 protein kinases, and consequently inhibits NF-κB p65 phosphorylation and the release of inflammatory factors such as xanthine oxidase (XOD), prostaglandin E2 (PGE2), TNF-α, IL-1β, and COX-2.

Furthermore, under inflammatory conditions, polydatin exhibited anti-inflammatory roles by improving AMP-activated protein kinase (AMPK)/sirtuin1 (Sirt1) signaling. Regarding NLRP3 inflammasome suppression, polydatin can inhibit the activation of the NLRP3 inflammasome and cleavage of caspase-1, thereby inhibiting pyroptosis and secretion of inflammatory cytokines, and promoting autophagy through the NLRP3/mTOR pathway.

4.3 Neuroprotective Signaling

Another mechanism of the neuroprotective effect of polydatin is mediated by the CCAAT/enhancer-binding protein β (C/EBPβ)/MALAT1/CREB/PGC-1α/PPARγ signaling pathway. This process results in silencing NF-κB-associated downstream inflammatory mediators, which could alleviate cerebral infarct volume and ameliorate the integrity of the blood–brain barrier (BBB).

Polydatin attenuated motor dysfunction in animal models of Parkinson's disease via lowering pro-inflammatory cytokines and microglial suppression. Inhibition of microglial activation leads to the decrement of dopaminergic neurodegeneration. Consequently, polydatin regulated the Akt/glycogen synthase kinase-3β (GSK-3β)/Nrf2/NF-κB signaling axis towards such effects. In addition, polydatin improved cell viability and Sirt1 expression.

4.4 Anticancer Mechanisms

PD could effectively inhibit the migration and proliferation of ovarian cancer cells, as well as the expression of the PI3K protein. The malignancy of lung cancer cells was reduced after PD treatments via targeting caspase 3, arresting cancer cells at the S phase, and inhibiting NLRP3 inflammasome by downregulation of the NF-κB pathway.

4.5 Cardiovascular Mechanisms

Polydatin (PD), one of the chief active ingredients of Rhizoma Polygoni Cuspidati, has been proved by modern pharmacological studies to possess extensive cardiovascular pharmacological activity, showing marked effects on protecting cardiomyocytes, dilating blood vessels, antagonizing platelet aggregation, thrombosis, and atherosclerosis. Polydatin treats atherosclerosis mainly from three aspects: anti-inflammatory properties, regulation of lipid metabolism, and anti-oxidative stress.

4.6 SIRT1-Mediated Mitochondrial Protection

Polydatin treatment has been shown to reverse high-glucose-induced mitochondrial dysfunction and ROS generation by promoting SIRT1-mediated mitochondrial biogenesis and Nrf2-mediated antioxidant signaling. Polydatin promotes the Nrf2-ARE anti-oxidative pathway through activating Sirt1 to resist AGEs-induced upregulation of fibronectin and transforming growth factor-β1 in rat glomerular mesangial cells.

5. Pharmacokinetics and Bioavailability

The absorption, distribution, and metabolism of polydatin are connected to its bioactivity. Polydatin might have higher bioavailability and a better antioxidant function compared to resveratrol. The bioavailability advantage derives from its glycosylated structure: although resveratrol has similar beneficial effects, its low bioavailability has remained a problem. Glycosylation increases solubility of resveratrol in an aqueous environment, thus improving its bioavailability.

Despite this structural advantage, some reviews note that in practice, the pharmacokinetic drawbacks of polydatin, including poor bioavailability, low solubility/selectivity, low plasma concentration, rapid metabolism, and chemical degradation, limit the associated therapeutic uses. Therapeutic activities of polydatin are constrained due to weak water solubility, chemical imbalance in aqueous alkaline medium, and substantial first-pass metabolism.

PD injection, applied in treating myocardial ischemia, cerebral ischemia, shock, and other cardiovascular and cerebrovascular diseases, has been approved to enter phase II clinical trials by the US Food and Drug Administration. PD has a favorable safety profile in animals (up to a dose of 200 mg/kg) and was well tolerated in humans (40 mg twice a day for 90 days in a phase II clinical trial).

6. Scientific Evidence by Area of Use

6.1 Cardiovascular Disease

Numerous pharmacological investigations of PD mainly focus on cardiovascular effects, neuroprotection, anti-inflammatory and immunoregulatory effects, anti-oxidation, anti-tumor, liver and lung protection.

Atherosclerosis: Preclinical evidence suggests polydatin may attenuate atherosclerosis through multiple pathways. Polydatin can inhibit the activation of the NLRP3 inflammasome and cleavage of caspase-1, thereby inhibiting pyroptosis and secretion of inflammatory cytokines, and promoting autophagy through the NLRP3/mTOR pathway in the setting of atherosclerosis. These findings derive from animal studies using ApoE knockout mice; no published controlled human trials for atherosclerosis exist at this time.

Diabetic Cardiomyopathy: Results from animal and cell studies demonstrated that PD inhibited hyperglycemia-induced myocardial injury and inflammatory fibrosis of diabetic cardiomyopathy models in vivo and in vitro. In another preclinical trial, 8-weeks of polydatin treatment significantly improved diastolic and systolic dysfunction, attenuated hypertrophy and interstitial fibrosis in mice with diabetes.

Coronary Heart Disease (Limited Human Data): The effectiveness of PD to treat elderly coronary heart disease has been described as definite in one reported clinical assessment. The evidence for the cardiovascular category overall is predominantly preclinical (animal models and cell culture); robust randomized controlled trials in humans remain limited.

6.2 Neuroprotection and Neurological Disorders

Polydatin has neuroprotective effects against Parkinson's disease (PD) through various mechanisms. Polydatin attenuated motor dysfunction in animal models of PD via lowering pro-inflammatory cytokines and microglial suppression.

Providing a novel delivery system could potentially help polydatin pass through the blood–brain barrier and develop a long-lasting therapeutic concentration of drugs in the CNS, while possessing fewer side effects. This observation highlights that current neuroprotective evidence is based primarily on animal models; blood–brain barrier penetration in humans has not been fully characterized.

Cerebral Ischemia: PD injection applied in treating myocardial ischemia, cerebral ischemia, shock, and other cardiovascular and cerebrovascular diseases has been approved to enter phase II clinical trials by the US Food and Drug Administration. This represents one of the more advanced stages of clinical development for polydatin, though published results of completed phase II trials in ischemia have not been broadly reported in the open literature.

Depression: Animal studies in mice have investigated polydatin's role in neuroinflammation and depression via the Sirt1/HMGB1/NF-κB signaling pathway. This evidence is limited to preclinical (mouse) models and cannot yet be translated to human outcomes.

6.3 Liver Protection (Hepatoprotection)

Polydatin, one of the natural active small molecules, was commonly applied in protecting and treating liver disorders in preclinical studies. Oxidative stress plays vital roles in liver injury caused by various factors, such as alcohol, viral infections, dietary components, drugs, and other chemical reagents. Oxidative stress is reported to be one of the main reasons in the progressive development of alcoholic liver diseases (ALDs), nonalcoholic liver diseases (NAFLDs), liver injury, fibrosis, hepatic failure (HF), and hepatocellular carcinoma (HCC).

Previous study has demonstrated that polydatin (PD) exerted antioxidant and anti-inflammatory effects and attenuated ethanol-induced liver damage. Additional animal studies have documented protection against CCl₄-induced liver injury and D-galactose-induced liver injury. Evidence strength: Primarily preclinical (animal and cell-based); human trials are absent from this area as of the available literature.

6.4 Metabolic Disease: Diabetes and Obesity

PD has demonstrated potential anti-hyperglycemic, anti-hyperlipidemic, anti-inflammatory, antioxidative stress, anti-hyperuricemic, and hepatoprotective effects in different metabolic disease animal and cell models, exhibiting promising prospects in treatment against metabolic disorders.

Obesity and Lipid Metabolism: In an investigation of the effects of PD on body weight control, glucose and lipid metabolic regulation, and anti-inflammation in a high-fat-diet-induced obese mouse model, after treatment with PD (100 mg/kg/d for 4 weeks), HFD mice reduced body weight, retroperitoneal fat mass, and adipose cell sizes; significantly lowered serum total cholesterol, triglyceride (TG), and LDL levels; and increased HDL levels compared with HFD control mice. These are animal study results.

Diabetic Nephropathy: PD treatment elevated Sirt1 and Nrf2 levels in the kidney tissues of diabetic rats, then improved the antioxidative capacity and renal dysfunction of diabetic models, and finally reversed the upregulation of fibronectin (FN) and TGF-β1. This is preclinical evidence in rodent models. The absence of clinical research for PD may attenuate the evidence of PD against metabolic diseases.

6.5 Anticancer Properties

Cancer poses a significant global health challenge. Polydatin, a stilbenoid compound abundant in various fruits and vegetables, has emerged as a promising candidate in cancer research. Renowned in traditional Chinese medicine for its multifaceted biological activities encompassing antioxidant, anti-inflammatory, anticancer, hepatoprotective, neuroprotective, and immunostimulatory effects, PD stands out as a versatile therapeutic agent.

In in vitro models, polydatin has been studied across multiple cancer types. PD could effectively inhibit the migration and proliferation of ovarian cancer cells, as well as the expression of the PI3K protein. The malignancy of lung cancer cells was reduced after PD treatments via targeting caspase 3, arresting cancer cells at the S phase, and inhibiting NLRP3 inflammasome by downregulation of the NF-κB pathway.

In colon cancer cell lines, polydatin was investigated for whether it might induce cell-cycle arrest and differentiation in human colorectal Caco-2 cells, and also examined in combination with resveratrol for possible synergistic effects. Evidence strength: All anticancer evidence for polydatin is currently in vitro (cell culture) or derived from animal tumor models. There are no published human clinical trials evaluating polydatin as an anticancer intervention. The evidence base is preliminary and exploratory.

6.6 Anti-inflammatory and Immunomodulatory Effects

Signaling pathways mediated by PI3K/Akt, MAPK, and transcription factors such as activator protein-1 (AP-1), NF-κB, and Nrf2 are the predominant cascades that participate in HO-1 expression, relevant to polydatin's anti-inflammatory actions.

Polydatin has been studied in mast cell-mediated allergic inflammation models, showing effects on PI3K/Akt, MAPK, NF-κB, and Nrf2/HO-1 pathways. These are cell and animal model findings, with no specific allergen-challenge human trials identified.

6.7 Pain and Gastrointestinal Conditions (Most Developed Human Evidence)

The most developed area of human clinical evidence for polydatin involves its use in combination with palmitoylethanolamide (PEA), tested in gastrointestinal and pelvic pain conditions.

Irritable Bowel Syndrome (IBS) — Randomized Controlled Trial: A pilot, 12-week, randomised, double-blind, placebo-controlled, multicentre study assessed the effect of palmitoylethanolamide/polydatin 200 mg/20 mg or placebo twice daily on low-grade immune activation, the endocannabinoid system, and symptoms in IBS patients. A total of 54 patients with IBS and 12 healthy controls were enrolled from five European centres. Compared with controls, IBS patients showed higher mucosal mast cell counts. The treatment did not significantly modify the IBS biological profile, including mast cell count. However, compared with placebo, palmitoylethanolamide/polydatin markedly improved abdominal pain severity (P < 0.05). The marked effect of the dietary supplement palmitoylethanolamide/polydatin on abdominal pain in patients with IBS suggests that this is a promising natural approach for pain management in this condition. Limitation: This was a pilot study of modest size; the contribution of polydatin specifically (vs. PEA) cannot be isolated.

Endometriosis-Related Pelvic Pain — Clinical Trials: A higher dosage (palmitoylethanolamide/polydatin at 400 mg/40 mg twice a day for 3 months) was tested in a clinical trial treating 21 patients with chronic pelvic pain related to endometriosis, and no significant side effects were reported. A meta-analysis of available studies found that in a heterogeneous sample of endometriotic patients with pain, the administration of micronized palmitoylethanolamide/trans-polydatin (400 mg/40 mg) twice a day for three months provided a clinically relevant improvement of chronic pelvic pain and dysmenorrhea while improving deep dyspareunia to a limited degree. However, four studies of poor quality were available. Evidence strength: Preliminary positive signals in small trials; limited by study number, quality, and inability to disaggregate polydatin's individual contribution from PEA.

6.8 Bone and Joint Disorders

To the best of available knowledge, there has been no clinical trial of polydatin specifically in patients with bone and joint disease. Preclinical in vitro studies have assessed polydatin in human osteoarthritic chondrocytes; polydatin did not cause observable cytotoxicity in human osteoarthritic chondrocytes at doses of up to 100 μg/mL. The inhibitory effect of polydatin on angiogenesis has led to investigation of its use to treat angiogenesis-related diseases, including retinopathy, rheumatoid arthritis, and psoriasis. All evidence in this domain remains preclinical.

6.9 Respiratory System

Various imperative biological activities have been suggested for polydatin towards promising therapeutic effects, including health-promoting roles on the respiratory system. Animal studies have investigated polydatin's effects against particulate matter (PM2.5)-induced lung injury, with preclinical results suggesting protective effects. No human clinical trials in respiratory conditions have been reported.

7. Body Systems Associated with Polydatin Research

Various imperative biological activities have been suggested for polydatin towards promising therapeutic effects, including anticancer, cardioprotective, anti-diabetic, gastroprotective, hepatoprotective, neuroprotective, anti-microbial, as well as health-promoting roles on the renal system, the respiratory system, rheumatoid diseases, the skeletal system, and women's health.

Cardiovascular system: Cardioprotection, atherosclerosis, platelet aggregation, vascular dilation
Central nervous system: Neuroprotection in ischemia, Parkinson's disease models, Alzheimer's disease models, traumatic brain and spinal cord injury models
Hepatic system: Alcoholic liver disease, NAFLD, drug-induced liver injury, fibrosis
Renal system: Diabetic nephropathy, oxidative stress-related renal injury
Metabolic system: Glycemic regulation, lipid metabolism, anti-obesity
Gastrointestinal system: IBS (human trial), gastroprotection
Reproductive/gynecological system: Endometriosis-related pain (human trial), women's pelvic health
Skeletal/musculoskeletal system: Bone density, osteoarthritis, rheumatoid arthritis (preclinical only)
Respiratory system: PM2.5 protection (preclinical only)
Immune system: Mast cell modulation, NLRP3 inflammasome suppression

8. Dosage Forms and Reported Dosages

Polydatin has been studied and used in a range of formulations and doses. The following are dosages reported in identified sources; they are not prescriptive recommendations.

Phase II clinical trial (FDA-approved entry): Polydatin 40 mg twice a day for 90 days was well tolerated in humans.
IBS randomized controlled trial: Palmitoylethanolamide/polydatin at 200 mg/20 mg twice daily for 12 weeks.
Endometriosis clinical trial: Palmitoylethanolamide/polydatin at 400 mg/40 mg twice a day for 3 months.
IBS safety assessment: Palmitoylethanolamide/polydatin at 200 mg/20 mg per day for 12 weeks in a phase II clinical trial, with a safety profile similar to placebo.
Animal study (mice, metabolic/obesity model): PD at 100 mg/kg/day for 4 weeks reduced body weight and improved lipid parameters.
Plant extract clinical study: One clinical study used an oral extract of P. cuspidatum 200 mg containing resveratrol 40 mg over 6 weeks for anti-inflammatory effect.

Although used for various applications, few clinical studies validate claims and guidance regarding dosing or safety is limited. Clinical evidence on which to base dosing guidelines is limited.

9. Safety Considerations and Interactions

9.1 General Safety Profile

Polydatin has low toxicity to humans, animals, and cells. The safe evaluation was completed by the New Drugs Safety Evaluation and Research Center in the Chinese Academy of Medical Sciences, which demonstrated that no significant toxic effect existed after intravenous injection of PD for 30 days.

In developmental toxicity testing using zebrafish embryos, polydatin at concentrations up to 435 μM showed no toxicity. Throughout the exposure period, zebrafish embryos exposed to polydatin exhibited normal development, with no significant mortality observed.

An intraperitoneal injection of 100 mg/kg polydatin caused neither death nor abnormal neurobehavior in mice.

9.2 Human Tolerability Evidence

In a phase II clinical trial treating both patients with irritable bowel syndrome and healthy controls with palmitoylethanolamide/polydatin at 200 mg/20 mg per day for 12 weeks, a safety profile similar to that of the placebo (cellulose) was obtained. A higher dosage (palmitoylethanolamide/polydatin at 400 mg/40 mg twice a day for 3 months) was tested in another clinical trial treating 21 patients with chronic pelvic pain related to endometriosis, and no significant side effects were reported.

9.3 Limitations of the Current Safety Data

There are few reports on drug toxicology and safety of polydatin, which may make analysis of risks inaccurate. The absence of clinical research for PD may attenuate the evidence of PD against metabolic diseases. PD activity was affected by various factors, such as dosage, approach, frequency of administration, species, and processing methods.

9.4 Potential Drug Interactions

Due to its structural similarity to resveratrol, polydatin may inhibit CYP450 enzymes (particularly CYP3A4 and CYP2C9), potentially increasing plasma levels of anticoagulants like warfarin and certain statins. These interactions are theoretical, derived from structural analogy with resveratrol; they have not been directly demonstrated in polydatin-specific human pharmacokinetic studies.

9.5 Estrogenic Activity

Polydatin has demonstrated estrogenic activity in preclinical models, making it potentially contraindicated for individuals with hormone-sensitive conditions such as estrogen receptor-positive breast cancer. This is a preclinical observation; no human studies have evaluated this risk specifically.

9.6 Pregnancy and Lactation

Use during pregnancy is not recommended. Avoiding use during lactation is also advised because information is lacking.

10. Overall Evidence Assessment

As of the most recent reviewed literature, polydatin has a well-characterized preclinical profile supported by a substantial body of animal and cell-based research. A great number of pharmacological and pharmacokinetic investigations in the past 22 years have demonstrated that PD has favorable therapeutic properties, indicating its potential as an effective material. However, further research is needed to explore its molecular mechanisms of action and definitive target proteins.

The strongest human clinical evidence is in pain management — specifically, the combination product palmitoylethanolamide/polydatin for IBS-related abdominal pain and endometriosis-related pelvic pain — where randomized, placebo-controlled data exist, although with the caveat that polydatin's individual contribution cannot be fully isolated from the PEA component. The need to develop further clinical trials and novel delivery systems of polydatin is considered essential to reveal new insights to researchers.

For all other therapeutic areas — including neuroprotection, hepatoprotection, anticancer effects, and metabolic disease — evidence remains at the preclinical stage (animal models and cell culture), and extrapolation to clinical outcomes in humans is premature based on current available data.

References

Condiciones de Salud

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Daño por Radicales LibresCientífico
Polydatin (a natural precursor of resveratrol) was co-administered with micronized PEA in a 6-month pilot open-label bicentric study (Cervigni et al., Biomed Res Int 2019; PMC6885282) in 32 refractory IC/BPS patients, demonstrating significant and progressive pelvic pain reduction (p<0.0001) and improved validated IC symptom questionnaire scores.

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