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Pterostilbene

Pterostilbene is a dimethylated derivative of resveratrol that, for some mechanisms, is more potent. It is also much better absorbed, and is commonly referred to as a 'better resveratrol'. It looks promising, but has significantly less research than its predecessor.

Our evidence-based analysis on pterostilbene features 55 unique references to scientific papers.

Kamal Patel
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Summary of Pterostilbene

Primary Information, Benefits, Effects, and Important Facts

Pterostilbene is a methylated stilbene molecule with structural similarity to resveratrol, the only difference being two methoxy groups on the pterostilbene molecule that replace hydroxy groups on the resveratrol molecule. While most of the actions of the two are comparable, pterostilbene appears to be much more well absorbed following oral ingestion and may be a more potent antioxidant and anticancer molecule.

Only one study has evaluated pterostilbene in humans. It found an increase in LDL-cholesterol and a trend towards lower HDL levels in people with high cholesterol levels who took 100 or 250 mg per day. It was unclear if the lower dose led to a reduction in blood pressure, but the reduction in the group who took the higher dose was potent.

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Things To Know & Note

Other Functions:

Primary Function:

Also Known As

trans-3, 5-dimethoxy-4-hydroxystilbene, 3, 5-dimethoxy-4-hydroxystilbene

Do Not Confuse With

Resveratrol (different molecule also from grapes)

Goes Well With

Caution Notice

Examine.com Medical Disclaimer

How to Take Pterostilbene

Recommended dosage, active amounts, other details

Supplementation of pterostilbene for the purpose of aiding glucose and lipid metabolism tends to be around 20- 40mg/kg oral ingestion in rats, which is an estimated human dosage range of:

  • 215-430mg for a 150lb person

  • 290-580mg for a 200lb person

  • 365-730mg for a 250lb person

Possible anxiolytic properties of pterostilbene are seen at 1-2mg/kg in mice, which is an estimated human dose of:

  • 5.5-11mg for a 150lb person

  • 7.3-14.5mg for a 200lb person

  • 9-18mg for a 250lb person

Which is notable as 5-10mg/kg in these mice (slightly over double the dose) has failed to have the same anxiolytic effects, suggesting a bell-curve that may favor lower dosages such as is found in food consumption rather than higher dosages from supplementation.

Limited human studies have used either 50mg twice a day or 125mg twice a day, and the addition of Grape seed extract (100mg at both dosing times) with the low dose may mitigate some adverse effects on cholesterol seen with pterostilbene in isolation.

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Human Effect Matrix

The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects pterostilbene has on your body, and how strong these effects are.
Grade Level of Evidence
Robust research conducted with repeated double-blind clinical trials
Multiple studies where at least two are double-blind and placebo controlled
Single double-blind study or multiple cohort studies
Uncontrolled or observational studies only
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Outcome Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
Notes
grade-c
Blood Pressure
Minor - See study
Pterostilbene appears to reduce blood pressure in hypercholesterolemic adults, and the addition of grape seed extract (which mitigates adverse cholesterol effects) adds to the benefits to blood pressure.
grade-c
HDL-C
Minor - See study
In hypercholesterolemic adults not on cholesterol lowering medication, pterostilbene appears to reduce HDL mildly.
grade-c
LDL-C
Minor - See study
An increase in LDL cholesterol has been noted with oral ingestion of pterostilbene in hypercholesterolemic adults, mitigated by grape seed extract
grade-c
Total Cholesterol
Minor - See study
An increase in total cholesterol, attributable to LDL, has been seen in hypercholesterolemic adults given pterostilbene.
grade-c
Weight
Minor - See study
A slight decrease in weight has been seen in adults given pterostilbene supplementation alongside an increase in cholesterol; the two appear linked, as the addition of grape seed extract appeared to mitigate both.
grade-c
Blood Glucose
- - See study
Supplementation of pterostilbene in hypercholesterolemic adults does not appear to influence blood glucose relative to control.
grade-c
Creatinine
- - See study
Supplementation of pterostilbene in hypercholesterolemic adults does not appear to influence creatinine relative to control.
grade-c
Liver Enzymes
- - See study
Supplementation of pterostilbene in hypercholesterolemic adults does not appear to influence liver enzymes (ALP, AST) relative to control.
grade-c
Triglycerides
- - See study
There do not appear to be any interactions on triglycerides in adults with normal triglyceride levels given pterostilbene supplementation.

Studies Excluded from Consideration

  • Confounded with the inclusion of other nutrients[1]

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Scientific Research on Pterostilbene

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1Sources and Structure

1.1Sources

Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene[2]) is a stilbene compound that is structurally similar to other popular stilbenes such as resveratrol or piceatannol;[3] it is named after its first discovered source (the pterocarpus genus)[4] but is also a component of blueberries and grape products. It is a phytoalexin (compound produced by plants as a defense against parasites and insects) similar to resveratrol[5] albeit more potent.[6][7]

Pterostilbene is a phytoalexin (plant chemical defense) similar to resveratrol, belonging to the stilbene class of molecules; it is named after the pterocarpus genus of plants

Its sources include:

  • Pterocarpus marsupium (Indian Kino Tree)[8] and pterocarpus santalinus (Sandalwood)[9]

  • Blueberries (92-550ng/g dry weight)[10][3]

  • Grape (Vitis vinifera) leaves[7] and berries[11]

  • Anogeissus acuminata[12]

  • The Dracaena genus[13]

  • Rheum rhaponticum (root)[14]

  • Peanuts (Arachis hypogaea)[15]

Pterostilbene is contained in low quantities in a few plants, most notably blueberries and grapes. Despite being in low concentrations, it is likely bioactive following oral ingestion of these fruits and their products (such as wine)

1.2Structure and Properties

The structure of pterostilbene is very similar to resveratrol, although the 3,5-dihydroxy part of resveratrol (the two hydroxyl groups on the benzene ring to the left) are replaced with methoxy groups.

The antioxidant capacities of resveratrol requires that there is a hydroxylation at the 4' position (right side of the molecule) and that the overall molecule is in a trans configuration rather than cis.[16][17][18][19] The above stilbenes all abide by these requirements while others such as pinosylvin do not. The methoxy groups on perostilbene appear to allow a greater antioxidative capacity relative to resveratrol.[16][17]

Pterostilbene is a methoxylated resveratrol, essentially. It has a larger difference in structure from resveratrol than piceatannol (another common stilbene compound, which is more similar to resveratrol). These three structures form the common dietary stilbenes

2Pharmacology

2.1Absorption

Pterostilbene, due to the two methoxy groups, exhibits increased hydrophobicity and oral absorption relative to resveratrol.[20] Relative to the approximate 20% bioavailability of resveratrol following oral ingestion,[21] pterostilbene's is near 80% at oral doses of 56-168mg/kg[20] and a bit lower (59.2+/-19.6% when paired with 2-hydroxypropyl-β-cyclodextrin, a delivery system[22] that complexes pterostilbene[23]) at 15mg/kg.[24] The general idea of methylated flavonoids or polyphenols having greater absorption is well known.[25]

Taking pterostilbene by itself has been noted to have a lower bioavailability (15.9+/-7.8%) than when taken as part of a delivery system, and bioavailability is further significantly reduced when taken in a fasted state (less than 5.5%).[24] Increasing the dosage to 60mg/kg under these same conditions increases the bioavailability two-fold.[24]

Sublingual absorption of pterostilbene has a bioavailability of 25.8+/-13.1%.[24]

Pterostilbene appears to be well absorbed, and better absorbed than resveratrol. While its absorption is somewhat respectable (for a polyphenolic) at lower oral doses, higher oral doses appear to actually be better absorbed than lower doses. Pterostilbene can be absorbed sublingually

2.2Serum

A single dose of 56-168mg/kg pterostilbene has noted a Cmax of 2,820ng/mL (56mg/kg) and 7,780ng/mL (168mg/kg) at a Tmax of 2 or 4 hours and half-lives of 90 and 114 minutes, respectively.[20]

56-168mg/kg pterostilbene daily for two weeks has noted a Cmax of 2,550ng/mL (56mg/kg) or 5,560ng/mL (168mg/kg) at a Tmax of 2 and 8 hours with half-lives of 96 and 114 minutes, respectively.[20] Repeated dosing appears to be associated with a higher overall AUC for 56mg/kg (15,000ng/h/mL versus 13,700ng/h/mL) but not 168mg/kg (49,600ng/h/mL versus 57,700ng/h/mL).[20]

Chronic dosing of pterostilbene appears to reduce the peak serum values while prolonging the time to reach peak levels. When looking at overall bodily exposure to pterostilbene, there isn't a predictable difference

2.3Distribution

The clearance rate of pterostilbene suggests that it readily bioaccumulates in the body[20] and the twin methoxy groups on the molecule mean it can diffuse into a cell more readily than resveratrol.[26]

2.4Metabolism

While resveratrol appears to mostly be metabolized into a glucuronide conjugate, pterostilbene is mostly metabolized into pterostilbene sulfate.[20]

2.5Enzymatic Interactions

Pterostilbene has been noted to activate AMPK (albeit in prostatic cancer cells).[27]

3Neurology

3.1Neuroinflammation

10-30μM pterostilbene appears to reduce microglial nitric oxide production when stimulated by LPS[28] without directly scavenging the nitric oxide radicals.[29] It appears to work via inhibiting IκBα phosphorylation, and is slightly more potent than resveratrol.[29]

3.2Anxiety

Pterostilbene appears to exert anxiolytic effects in the 1-2mg/kg oral dosing range in mice subjected to an elevated maze test, although it appears ineffective at 5-10mg/kg; this is thought to be related to ERK phosphorylation in the hippocampus[30] which is known to be related to anxiety and mood.[31]

3.3Memory and Learning

Isolated pterostilbene has been noted to improve cognition in aged rats when fed in the diet at 0.004-0.016% over 12-13 weeks, with the improvements correlating with hippocampal concentrations of pterostilbene.[32]

4Cardiovascular Health

4.1Blood Pressure

Supplementation of pterostilbene at 125mg twice daily appeared to reduce blood pressure (diastolic and systolic) in hypercholesteromic adults, an effect not observed with 50mg taken twice daily but partially replicated (systolic only) when 50mg was paired with 100mg grape seed extract (GSE) also taken twice daily.[33]

4.2Cholesterol

Pterostilbene has been noted to increase the signalling of PPARα receptors at 100µM (8-fold) and 300µM (14-fold) concentrations, with 100µM of pterostilbene being 74.2% more effective than 100µM ciprofibrate as assessed by relative luciferase units.[34] At concentrations of 1-10µM pterostilbene, the receptors were mostly inactive.[34] Since pterostilbene is known to bind to PPARα[35] it appeared to be an agonist of this receptor.

Pterostilbene may be a PPARα ligand

Oral ingestion of pterostilbene at 25mcg/kg of the diet of hamsters with high cholesterol is able to subsequently reduce LDL-C (29%) and increase HDL-C (7%),[34] and reductions in LDL-C (57%) and improvements in HDL-C (73.1%) have been noted in diabetic rats given 40mg/kg pterostilbene.[36]

Animal studies show an improvement in cholesterol metabolism with low dose supplementation of pterostilbene

When supplemented to subjects with high cholesterol (200mg/dL) and high LDL-C, pterostilbene at both doses (50mg or 125mg, both taken twice daily) appeared to increase total cholesterol and LDL cholesterol relative to placebo, with the group given the low dose pterostilbene with grape seed extract (GSE; 100mg twice daily) not seeing this increase;[33] the benefits to blood pressure seen with high dose pterostilbene were replicated with GSE.[33]

HDL cholesterol was noted to be unchanged overall, but in people not on cholesterol medication taking the higher dose of pterostilbene there was a decrease relative to control.[33]

High doses of pterostilbene supplementation (50-125mg twice daily) appear to increase, rather than decrease, cholesterol and LDL levels in subjects who already have high LDL concentrations; those not on cholesterol lowering medications also noted a decrease in HDL cholesterol

4.3Triglycerides

Serum triglycerides were reduced by 30% following six weeks of supplementation with 40mg/kg pterostilbene in diabetic rats, the potency exceeding that of 500mg/kg metformin but not fully normalizing relative to nondiabetic control.[36]

In humans (hypercholesterolemic but with normal triglycerides) given 50mg or 125mg pterostilbene twice daily over the course of 52 days, there were no observable changes in serum triglyceride concentrations relative to control; the addition of 100mg grape seed extract to the low dose group also did not confer any beenfits.[33]

5Interactions with Glucose Metabolism

5.1Blood Glucose

25mcg/kg of pterostilbene to the diets of hypercholesterolemic hamsters is able to reduce blood glucose by 14%[34] and in diabetic rats 40mg/kg pterostilbene for six weeks a reduction in glucose with a concomitant increase in insulin was noted;[36] this extended to otherwise healthy rats to a lesser degree (6.3% reduction)[36] and in hyperglycemic rats the potency of pterostilbene (40mg/kg) is comparable to metformin (500mg/kg).[36][37]

6Inflammation and Immunology

6.1Mechanisms

Pterostilbene has been noted to inhibit LPS-induced PGE2 production from white blood cells with an IC50 value of 1.0+/-0.6µM (compared to the IC50 of resveratrol at 3.2+/-1.4µM)[4] and can inhibit iNOS activity in macrophages with an IC50 of 9.9µg/mL (comparable to resveratrol and weaker than parthenolide from feverfew at 0.42µg/mL).[15]

Pterostilbene may exert antiinflammatory effects at low concentrations with a potency greater than resveratrol; these effects may be relevant to oral supplementation of higher doses of pterostilbene

Neutrophils are known to produce oxidation when activated via the NADPH oxidase enzyme[38] which may lead to injury in excessive levels (despite being protective against bacterial invaders at lower activity);[39] resveratrol has previously been implicated as an NADPH oxidase inhibitor, and this activity appears to extend to pterostilbene as it can reduce chemiluminescence of neutrophils (an indication of antioxidant activity[40]).[41] And while pterostilbene doesn't inherently affect superoxide levels in neutrophils,[42] 100µM is able to reduce superoxide production and subsequent myeloperoxidase (MPO) production to around 60% of control with lower concentrations ineffective.[42]

When comparing potencies, pterostilbene appears to be less effective than resveratrol[43] (assessed by IC50 values of reducing extracellular chemiluminescence) with pterostilbene also being less potent than piceatannol, and the potency of curcumin lying between resveratrol and piceatannol.[44][41][45] When looking at intracellular chemiluminescence, curcumin seems most potent (IC50 3.57µM to pterostilbene's 21.58µM) and resveratrol is intermediate to the two.[43]

Reduced chemiluminescence has been noted in rats following ingestion of 30mg/kg pterostilbene (partial reduction), suggesting that the above is biologically relevant in higher doses to a small degree.[46]

Pterostilbene appears to reduce oxidation in neutrophils (the main mechanism of action of spirulina), although the effect seems to occur only at very high concentrations. It appears to be active following oral ingestion, but not to a large degree

6.2Joint Inflammation

30mg/kg pterostilbene in a rat model of arthritis has shown weak anti-inflammatory effects, having no significant effect on hind paw volume (a marker of edema) or MPO while minorly reducing chemiluminescence (a marker of neutrophil oxidation).[46]

Current preliminary evidence suggests no significant benefit of pterostilbene on inflammation, just a minor antioxidative effect

7Interactions with Cancer Metabolism

7.1Lung

Resveratrol has previously been noted to increase apoptosis via the Notch signalling pathway[47][48] (which induces Cyclin D1 and survivin as it is prosurvival[49][50]) which appears to extend to pterostilbene in lung cancer cells (A549) with an IC50 value on cell growth of 3.476µM.[51] Pterostilbene appears to reduce the Notch1-dependent survial while induces production of reactive oxygen species, leading to apoptosis.[51]

Pterostilbene appears to reduce viability of lung cancer cells in vitro, and does so at a concentration that is probably relevant to oral supplementation

8Longevity and Life Extension

8.1Mechanisms

Pterostilbene (70μM) has been noted to upregulate a variety of mitochondrial genes in a yeast assay (148 up and 13 downregulated) involved in respiration, electron transport, mitochondrial protein targeting, and mitochondrial protein synthesis.[52]

The oxidative stress seen during the aging process in neurons appears to be attenuated with low dietary levels of pterostilbene (0.004-0.016% of the diet), with a potency greater than resveratrol.[32][53]

9Safety and Toxicology

9.1General

In mice, doses of pterostilbene up to 3,000mg/kg daily (500-fold the estimated human intake) have failed to exert any significant clinical or biochemical toxicity.[54]

Pterostilbene up to 250mg daily (125mg twice daily) in humans over the course of 6-8 weeks has failed to cause any biochemical or clinical signs of toxicity, with side effects not significantly different than placebo aside from one dropout due to worsening cholesterol[55] which may be related to an increase in LDL-C seen with this dose when tested elsewhere in hypercholesterolemic adults.[33]

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