Dimethylresveratrol

Other Names

(E)-Pterostilbene3',5'-Dimethoxy-4-stilbenol3',5'-Dimethoxy-4E-stilbenol3',5'-Dimethoxy-4trans-stilbenol3',5'-Dimethoxy-resveratrol3,5-Dimethoxy-4'-hydroxy-trans-stilbene3,5-Dimethoxy-4'-hydroxystilbene4-(2-(3,5-Dimethoxyphenyl)ethenyl)phenol4-Stilbenol, 3',5'-dimethoxy-, (E)-4-trans-(2-(3,5-Dimethoxyphenyl)ethenyl)phenol4-[(1E)-2-(3,5-Dimethoxyphenyl)ethenyl]phenol4-[(E)-2-(3,5-Dimethoxyphenyl)ethenyl]phenol4-[(E)-2-(3,5-Dimethoxyphenyl)vinyl]phenolPhenol, 4-((1E)-2-(3,5-dimethoxyphenyl)ethenyl)-Phenol, 4-(2-(3,5-dimethoxyphenyl)ethenyl)-, (E)-Phenol, 4-[(E)-2-(3,5-dimethoxyphenyl)ethenyl]-PterostilbeneResveratrol dimethyl ethertrans-3,5-Dimethoxy-4'-hydroxystilbenetrans-Pterostilbene

Synopsis

Dimethylresveratrol (Pterostilbene): A Comprehensive Encyclopedic Reference

1. Identity: Chemical Names, Botanical Sources, and Structural Characteristics

1.1 Nomenclature and Chemical Identity

Pterostilbene (trans-3,5-dimethoxy-4′-hydroxystilbene) is a natural dimethylated analogue of resveratrol, and is a stilbenoid phytochemical compound. The compound is commonly referred to by the names pterostilbene, dimethylresveratrol, 3,5-dimethoxy-4′-hydroxystilbene, and trans-pterostilbene. It carries CAS number 537-42-8, with the molecular formula C₁₆H₁₆O₃, and a molecular weight of 256.30.

Pterostilbene (PTS) is a natural polyphenol and a dimethyl ether analog of resveratrol. Structurally, it belongs to the stilbene class of compounds — a subclass of non-flavonoid polyphenols characterized by a trans-stilbene backbone. The key structural distinction from resveratrol is that the replacement of two hydroxyl groups with methoxy groups in pterostilbene enhances its bioactivity and oral bioavailability and indicates a prolonged metabolism. Specifically, these two methoxy groups are located at the 3 and 5 positions of the A-phenyl ring, while a free hydroxyl group is retained at the 4′ position of the B-phenyl ring.

1.2 Botanical Sources and Natural Occurrence

Pterostilbene is a stilbenoid chemically related to resveratrol. In plants, it serves a defensive phytoalexin role. It is found in almonds, various Vaccinium berries (including blueberries), grape leaves and vines. It is also encountered in the xylem, particularly in the heartwood of Pterocarpus marsupium as well as in other species of the Pterocarpus family, including Malay padauk, the Narra tree (Pterocarpus indicus), Muninga, and African padauk (Pterocarpus erinaceus), thus contributing to the high natural durability of those woods as a known phytoalexin.

PTS is produced by plants as a secondary metabolite that serves to respond to environmental challenges, including UV radiation, drought, fluctuating temperature extremes, grazing pressures, and fungal infections, and PTS serves as an important mediator of disease resistance. Similar to resveratrol, PTS also behaves as a phytoalexin, conferring crucial anti-pathogenic defense to plants.

Pterostilbene is a natural 3,5-dimethoxy analog of resveratrol. This stilbene compound has a strong bioactivity and exists widely in Dalbergia and Vaccinium spp. Besides natural extraction, pterostilbene can be obtained by biosynthesis.

Pterostilbene is also abundant in the Chinese dragon's blood, a rare and valuable traditional Chinese medicine with a long history of medical use, reaching up to 2–4 mg/g.

1.3 Quantitative Occurrence in Food Sources

The concentration in blueberries ranges from 9.9 to 15.1 mg/kg of blueberries fresh weight, 0.2 to 4.7 mg/g of the weight of the skin of fungus-infected grapes, 99 to 151 ng/g dried sample of rabbit-eye blueberry (Vaccinium ashei), and 520 ng/g dried sample of deerberries (Vaccinium stamineum). Additionally, peanut (Arachis hypogaea) has also been identified as a source of PTS.

Pterostilbene was found in two cultivars of V. ashei and in V. stamineum at levels of 99–520 ng/g dry sample, as determined by GC-MS analysis of Vaccinium berry extracts. These levels are notably low, meaning that the amounts available from ordinary food consumption are a small fraction of the doses used in clinical research.

1.4 Common Supplemental Forms and Preparations

Pterostilbene is commercially available as a dietary supplement primarily in oral dosage forms, including capsules and tablets containing the isolated compound. The compound has also been studied in nutraceutical compositions as crystalline polymorphs with potential pharmaceutical applications. Combination products pairing pterostilbene with nicotinamide riboside (NR) to support NAD⁺ metabolism have also entered the market; one such product is a combination of NR and pterostilbene, described as a naturally occurring analog of the polyphenol resveratrol found to be a potent SIRT1 activator.

2. Traditional and Historical Use

2.1 Ayurvedic and South Asian Tradition

The traditional use of dimethylresveratrol is inseparable from the traditional use of its primary botanical source, Pterocarpus marsupium (Indian Kino Tree), known as Vijaysar in Ayurvedic texts. Pterocarpus marsupium (Vijaysar) is a deciduous tree considered to have high insulinogenic properties. Since ancient times, Ayurveda practitioners believed that the heartwood of Vijaysar significantly reduced blood sugar levels in diabetes.

Pterocarpus marsupium is an important medicinal plant belonging to the family Fabaceae and commonly known as the Indian Kino tree or Bijasal. It plays an important role in Ayurveda, Homeopathic, and Unani systems of medicine. In Ayurveda, mainly the cup made from the heartwood is used for drinking water to control blood sugar. The plant is loaded with diverse bioactive compounds like pterosupin, pterostilbene, liquiritigenin, epicatechin, and kinotannic acid, and hence shows antidiarrheal, anticancer, and antibacterial activities.

The wooden glass made up of the heartwood of Pterocarpus marsupium was used for drinking water to control blood sugar in the Ayurvedic system of medicine (references citing Jain, 1968; Chopra et al., 1958). In addition to diabetes management, pterostilbene abundant in blueberries and grapes has been used in Ayurvedic medicine as a cardiotonic, astringent, anti-diarrheal, and antacid.

Ethnobotanical uses of P. marsupium include its application as an anti-inflammatory, antimicrobial, anti-diabetic, and for treating various ailments like dysentery, fever, and skin diseases. Ayurveda advocates the hardwood rather than the bark of P. marsupium to treat diabetes.

2.2 Constituents Identified as Active in the Traditional Source

Marsupsin, pterosupin, and pterostilbene are the three important phenolic constituents of the heartwood of P. marsupium reported to significantly lower blood glucose levels. Scientific isolation of pterostilbene from this plant and from other species helped establish that the compound is one of the principal bioactive agents in the traditionally used heartwood preparations. Pterostilbene has been isolated from various plant sources including the heartwood of Pterocarpus santalinus, Pterocarpus marsupium, and leaves of Vitis vinifera.

The Indian traditional system of medicine prescribed plant therapies for diseases including diabetes mellitus, called madhumeh in Sanskrit. One such plant mentioned in Ayurveda is Pterocarpus marsupium (PM). The Indian Council of Medical Research (ICMR) later conducted a clinical trial; an aqueous extract of the heartwood of P. marsupium was tested clinically and found effective in non-insulin-dependent diabetes mellitus patients (ICMR, 1998).

3. Key Constituents, Structural Chemistry, and Mechanisms of Action

3.1 Structural Features Governing Bioactivity

Pterostilbene is a naturally occurring dimethyl ether analog of resveratrol distinguished by two methoxy groups at the 3 and 5 positions of the A-ring. This structural modification confers increased lipophilicity and resistance to hepatic phase II metabolism (notably glucuronidation and sulfation), resulting in significantly greater oral bioavailability (upwards of 80% in rodent models) compared to resveratrol (less than 20%).

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 a high volume of distribution at steady state (Vss), which suggests extensive tissue distribution.

Pterostilbene can be rapidly absorbed and is widely distributed in tissues, but it does not seriously accumulate in the body. Pterostilbene can easily pass through the blood-brain barrier because of its low molecular weight and good liposolubility.

3.2 Primary Molecular Targets and Signal Pathways

Pterostilbene's mechanisms of action include activation of Nrf2, the transcription factor that regulates antioxidant defenses, and activation of the AMPK/SIRT1/PGC-1α axis important for energy and mitochondrial homeostasis.

Mechanistically, pterostilbene modulates several molecular cascades relevant to metabolic homeostasis, neuroprotection, and redox regulation. It acts as an agonist at peroxisome proliferator-activated receptors (PPARα/γ), supports AMP-activated protein kinase (AMPK) activation in hepatic tissue, and inhibits NF-κB-mediated inflammatory gene transcription downstream of multiple stressors. Preclinical studies indicate modulation of SIRT1 signaling pathways implicated in mitochondrial biogenesis and synaptic plasticity.

Various studies indicate that PTS exhibits anti-inflammatory, antioxidant, and antitumour properties. Its influence on regulatory pathways like NF-κB and PI3K/Akt underscores its diverse strategies in addressing diseases.

Pterostilbene exerts its bioactivities through a variety of mechanisms. It exerts its anti-tumor effect by regulating a variety of signaling pathways and plays a neuroprotective role by improving and reducing the volume of cerebral infarction, inhibiting apoptosis, and protecting the integrity of the blood-brain barrier. Antioxidant and anti-inflammatory activities serve as the basis for the various bioactivities of pterostilbene. In addition, pterostilbene shows hypoglycemic, lipid-lowering, antifungal, antiviral, and antipsychotic activities.

Several studies have demonstrated pleiotropic pharmacological activities of PTS including anti-inflammatory, antioxidant, anticancer, analgesic, and inhibition of histone deacetylase-1 (HDAC1).

In studies of nonalcoholic fatty liver disease, pterostilbene significantly ameliorated FFA-induced steatosis in HepG2 cells and enhanced lipolysis through the upregulation of SIRT1/AMPK and insulin signaling pathways. In in vivo studies, treatment resulted in reduced hepatic lipid droplet accumulation. The data showed that pterostilbene upregulated the SIRT1/AMPK pathway and subsequently downregulated the protein expression of SREBP-1 to activate fatty acid β-oxidation and inhibit fatty acid synthesis.

4. Scientific Evidence by Area of Use

4.1 Cardiometabolic Effects: Blood Pressure and Lipids

The most important human clinical evidence for pterostilbene comes from a prospective, randomized, double-blind, placebo-controlled trial (registered as NCT01267227). This study enrolled 80 patients with a total cholesterol ≥200 mg/dL and/or LDL ≥100 mg/dL and divided them into four groups: (1) pterostilbene 125 mg twice daily; (2) pterostilbene 50 mg twice daily; (3) pterostilbene 50 mg + grape extract (GE) 100 mg twice daily; (4) matching placebo twice daily for 6–8 weeks. Endpoints included lipids, blood pressure, and weight.

Blood pressure: Both systolic (−7.8 mmHg; P < 0.01) and diastolic blood pressure (−7.3 mmHg; P < 0.001) were reduced with high-dose pterostilbene.

LDL cholesterol: A notable and clinically significant finding was an adverse lipid effect. LDL increased with pterostilbene monotherapy (17.1 mg/dL; P = 0.001), which was not seen with the GE combination (P = 0.47). Presence of a baseline cholesterol medication appeared to attenuate LDL effects. Patients not on cholesterol medication (n = 51) exhibited minor weight loss with pterostilbene (−0.62 kg/m²; P = 0.012).

The overall conclusion of this trial was that pterostilbene increases LDL and reduces blood pressure in adults. These are contradictory clinical findings that limit straightforward recommendations regarding its cardiometabolic use. The sample size was small, the trial duration was 6–8 weeks, and the population was specifically those with hypercholesterolemia, so generalizability is limited.

In rodent preclinical studies, a different picture emerged for lipids. Pterostilbene reduced adipose tissue mass by −15.1% (15 mg/kg/day group) and −22.9% (30 mg/kg/day group). In adipose tissue, it decreased malic enzyme and fatty acid synthase activities. Pterostilbene significantly activates SIRT1 and PPARα in vitro. These animal findings have not been consistently replicated in human trials.

4.2 Blood Glucose and Diabetes-Related Effects

Pterostilbene is primarily found in Pterocarpus marsupium, which is a traditional herbal medicine used for the treatment of diabetes. Preclinical evidence supports antidiabetic effects. Manickam et al. (1997) examined the antihyperglycemic activity of the three major phenolics in the aqueous extract of P. marsupium hardwood, being marsupsin, pterosupin, and pterostilbene. Their findings indicate that treatment with marsupsin and pterostilbene in chemically induced (alloxan) diabetic rats decreased plasma glucose concentration and body weight.

Active compounds such as pterostilbene, along with flavonoids present in this tree, show potential in enhancing insulin sensitivity and promoting glucose metabolism. Numerous studies indicate that preparations from Pterocarpus marsupium bark, particularly extracts and powders, can have a profound impact on glucose levels in diabetic models.

In the principal human clinical trial (Riche et al., 2013/2014), there were no adverse drug reactions on hepatic, renal, or glucose markers based on biochemical analysis, though blood glucose was not a primary efficacy endpoint. In a rat study, animals receiving pterostilbene or resveratrol showed less body weight gain, and all tested stilbenes exhibited cholesterol-lowering effects. Robust human clinical trials specifically targeting blood glucose as a primary endpoint are lacking.

4.3 Neuroprotection and Cognitive Function

Pterostilbene has higher bioavailability than resveratrol. Studies in rodent models suggest cognitive benefits through antioxidative and anti-inflammatory effects. However, no clinical trials have confirmed these effects in humans. No studies have tested pterostilbene for the prevention of dementia or age-related cognitive decline in humans.

PTS has demonstrated neuroprotective effects in preclinical models of Alzheimer's disease and Parkinson's disease, potentially due to its anti-inflammatory, antioxidant, and anti-apoptotic properties. PTS effectively suppresses neuroinflammation, one of the key pathological features of neurodegenerative diseases, by inhibiting the activation of microglial cells.

Pterostilbene plays a neuroprotective role by improving neurological function, reducing the volume of cerebral infarction, inhibiting apoptosis, and protecting the integrity of the blood-brain barrier — findings all derived from animal models. Substantial evidence suggests that pterostilbene may have numerous preventive and therapeutic properties in a vast range of human diseases that include neurological, cardiovascular, metabolic, and hematologic disorders, though the bulk of this evidence remains preclinical.

4.4 Anticancer Properties

The antioxidant activity of pterostilbene has been implicated in anticarcinogenesis, modulation of neurological disease, anti-inflammation, attenuation of vascular disease, and amelioration of diabetes.

Pterostilbene has been reported to have powerful growth-inhibitory effects in several different types of cancer cells, notably breast, colon, and prostate cancer cells. Further benefits of pterostilbene have been reported in preclinical trials, in which pterostilbene was shown to be a potent anticancer agent in several malignancies. Although resveratrol has a wide range of health benefits, including anti-cancer properties, pterostilbene has a robust pharmacological profile that includes better intestinal absorption and increased hepatic stability compared to resveratrol.

In the context of melanoma, resveratrol serves as a substrate for tyrosinase, producing an o-quinone metabolite that is highly cytotoxic to melanocytes, and research has investigated whether PTS may also be metabolized by tyrosinase in a similar manner. It is critical to note that all anticancer evidence for pterostilbene to date comes from in vitro cell studies and animal models. No controlled human clinical trials have established clinical efficacy for cancer prevention or treatment.

4.5 Anti-inflammatory Activity

PTS has been documented to exert its beneficial effects mainly by modulating antioxidant, anti-apoptotic, and anti-inflammatory pathways. Of particular interest, the activation of the Nrf2 signaling pathway by PTS has been an essential focus of research.

Through attenuating the levels of oxidative stress markers such as 4-hydroxynonenal and 8-hydroxyguanosine, reducing lactate dehydrogenase leakage, reversing elevated MDA concentrations in the ischemic brain hemisphere, and restoring depleted SOD activity, PTS effectively neutralizes oxidative stress.

Pterostilbene has been shown to significantly reduce cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and nuclear factor kappa light chain enhancer (NF-κB) in preclinical models. These anti-inflammatory mechanisms have been extensively characterized in cell culture and animal studies; their translation to clinical outcomes in humans has not been validated in dedicated controlled trials.

4.6 Metabolic and Obesity-Related Effects

In a rodent study, a 0.5% pterostilbene diet markedly suppressed abdominal white adipose tissue (WAT) accumulation in obese rats. The oxygen consumption and energy expenditure were significantly higher in the pterostilbene group, and pterostilbene increased fat metabolism rather than carbohydrate metabolism in obese rats.

The mRNA level of uncoupling protein, a thermogenic regulator, was increased, and the mRNA levels of fatty acid synthase and leptin, which are involved in lipogenesis and fat storage, were markedly decreased in white adipose tissue after pterostilbene treatment. These findings are preclinical and obtained in rodent obesity models.

4.7 Cardiovascular Protection

Pterostilbene, a natural analog of resveratrol, is a known antioxidant and exerts myocardial protection. Research exploring its action and detailed mechanism on doxorubicin-treated cardiomyocytes found that both in vitro and in vivo studies revealed that pterostilbene inhibited acute doxorubicin exposure-caused oxidative stress and mitochondrial morphological disorder via PGC1α upregulation through activating AMPK and via PGC1α deacetylation through enhancing SIRT1. This represents preclinical evidence only.

5. Body Systems and Health Areas of Association

Cardiovascular system: Blood pressure reduction demonstrated in one human RCT; LDL cholesterol increase also documented in the same RCT; preclinical evidence of cardioprotective and anti-atherosclerotic effects.
Metabolic/endocrine system: Traditional and preclinical antidiabetic associations; hepatic lipid metabolism modulation via SIRT1/AMPK/SREBP-1 pathways in animal and cell models.
Central nervous system: Preclinical evidence of neuroprotection, cognitive benefit, reduction of neuroinflammation, and blood-brain barrier integrity; no human trial data.
Oncology: Preclinical antiproliferative and cytotoxic effects in multiple cancer cell lines; no human clinical evidence.
Immune/inflammatory system: NF-κB and Nrf2 pathway modulation demonstrated in cell and animal models.
Hepatic system: Preclinical evidence of protection against nonalcoholic fatty liver disease via lipid metabolism pathways.
Body weight regulation: Minor weight reduction observed as a secondary endpoint in one human RCT in a subpopulation not using statins.

Its wide range of positive health effects — including antioxidant, anticancer, estrogenic, anti-aging, anti-Alzheimer's, anti-hyperglycemic, anti-viral, anti-osteoporotic, anti-obesity, neuroprotective, and cardioprotective activities — is consistent with its diverse biological activities and its potential role in cancer chemoprevention, though most of these associations remain at the preclinical stage.

6. Dosage Forms and Reported Dosages

In the key human safety and metabolic parameters trial, subjects were divided into four groups: pterostilbene 125 mg twice daily (250 mg/day); pterostilbene 50 mg twice daily (100 mg/day); pterostilbene 50 mg + grape extract 100 mg twice daily; and matching placebo twice daily for 6–8 weeks.

The average study duration in this trial was 52 days.

In rodent anti-obesity studies, pterostilbene was administered at doses of 15 mg/kg body weight/day or 30 mg/kg body weight/day for 6 weeks.

In a rodent metabolomics study, pterostilbene was administered at a dose of 100 µmol/kg/day for a two-week daily oral administration.

In a mouse intracerebral hemorrhage model, pterostilbene was administered at 10 mg/kg by intraperitoneal injection once daily.

Human studies have used 100–250 mg/day in oral divided doses. The pharmacokinetic profile established in studies cited by Riche et al. (2013) indicates a half-life of 105 minutes and oral bioavailability of approximately 80% in animal studies.

7. Safety Considerations and Drug Interactions

7.1 Established Human Safety Data

In a double-blind randomized controlled trial that enrolled 80 people with high total or LDL cholesterol, pterostilbene treatment (50 mg or 125 mg twice daily) for 6–8 weeks did not result in any adverse drug reactions on liver, kidney, or glucose markers based on biochemical analyses. There were no major adverse events.

Pterostilbene is generally safe and well tolerated at doses up to 250 mg/day, with no adverse effects on hepatic, renal, or glucose markers. However, it may increase LDL cholesterol, requiring careful consideration of its lipid modulating effects. This LDL elevation is the most clinically significant finding from human trials to date.

LDL increased with pterostilbene monotherapy (17.1 mg/dL; P = 0.001), and the presence of a baseline cholesterol medication appeared to attenuate this LDL effect. This increase was not significant in the grape extract combination group (P = 0.47).

7.2 Drug–Enzyme Interactions (Phase I and Phase II Metabolism)

Herbal extracts and phytochemicals have the potential to interact with co-administered drugs through the inhibition or induction of drug metabolism mediated by UDP glucuronosyltransferase (UGT) and cytochrome P450 (CYP) enzymes. The CYP enzymes are the most important phase I xenobiotic-metabolizing enzymes; similarly, the UGT enzymes are the most important phase II xenobiotic-metabolizing enzymes. More than 90% of prescribed drugs are metabolized by CYPs and UGTs enzymes.

Pterostilbene significantly inhibited CYP2C8 and UGT1A6 activities in vitro. The IC₅₀ (mean ± SE) values for CYP2C8 and UGT1A6 inhibition were 3.0 ± 0.4 µM and 15.1 ± 2.8 µM, respectively; the volume per dose index (VDI) exceeded the predefined threshold of 5 L/dose for both CYP2C8 and UGT1A6, suggesting a potential for interaction in vivo.

CYP2C9 was the most inhibited enzyme in separate in vitro studies, with an approximate IC₅₀ value of 0.7 µM. Its volume per dose index (VDI) was significantly greater than the pre-identified cut-off at 50 L. The precise IC₅₀ value of pterostilbene for CYP2C9 inhibition was determined to be 0.12 ± 0.04 µM.

Inhibition of CYPs and UGTs enzymes in vivo may result in unexpected elevations in the plasma concentrations of concomitant drugs, leading to adverse effects. Few studies have investigated the effects of pterostilbene on UGT enzymes, particularly the inhibitory effects, which may increase the risk of food-drug interactions if co-administered with other medications.

Pterostilbene appears to block the activity of several metabolic enzymes, most notably CYP2C8 and UGT1A6, and may increase the effect of drugs they metabolize. For CYP2C8, these include the antimalarial drug amodiaquine, cerivastatin, repaglinide, torasemide, and certain chemotherapy drugs. For UGT1A6, these include acetaminophen and aspirin.

7.3 Evidence Strength and Limitations

There has been extensive animal research examining both the safety and efficacy of pterostilbene. Animal studies have demonstrated efficacy in cardiometabolics (e.g., cholesterol and blood glucose), as well as cancer and cognition mediators. However, translation to humans remains incomplete.

Pterostilbene activates SIRT1 and AMPK and lowers blood pressure in some trials, but has fewer published human studies than resveratrol. The trade-off between bioavailability and evidence depth is real.

Numerous studies that have evaluated PTS for its therapeutic potential have demonstrated its role as a promising candidate for health benefits in a broad spectrum of disease conditions. Various experimental studies have confirmed that PTS has anti-cancer, anti-diabetic, anti-hypertensive, antimicrobial, anti-aging, anti-atherosclerotic, and neuroprotective properties. The overwhelming majority of this evidence, however, is from in vitro and animal models, not human clinical trials. The only robust human RCT data available covers cardiometabolic markers (lipids, blood pressure, and safety biomarkers), and the observed LDL elevation is an important safety signal that warrants attention in any clinical assessment.

References

Health Conditions

Health conditions that Dimethylresveratrol may help support.

No conditions available.

Body Systems

Body systems that Dimethylresveratrol may help support.

No body systems available.