Herb-Drug Interactions: Grapeseed

Vitis vinifera L. (Vitaceae)

Synonym(s) and related species

Vitis vinifera is the Grape vine, of which there are many cultivars.


Grapeseed extract contains flavonoids, which include gallic acid, catechin, (—)-epicatechin, and their galloylated derivatives, and proanthocyanidins. Resveratrol, a polyphenolic stilbene derivative, and tocopherols and tocotrienols are also present.

Use and indications

Grapeseed extract is promoted as an antioxidant supplement for preventing degenerative disorders in particular, in the same way as other flavonoid-containing products. The in vitro antioxidant properties are well documented and there is some clinical evidence to suggest that it can promote general cardiovascular health.


An in vitro study found that grapeseed extract potently inhibits CYP3A4, but only when the catechin content is high. In contrast, another in vitro study found that grapeseed extract is a weak inducer of the cytochrome P450 isoenzyme CYP3A4. The author suggests that grapeseed therefore has the potential to cause interactions. However, the effect of grapeseed extract was less than that of omeprazole, which does not commonly interact by this mechanism, suggesting that any effect is unlikely to be clinically relevant. Furthermore, a study in rats suggests that grapeseed extract does not significantly alter the pharmacokinetics of midazolam0, a probe substrate for CYP3A4.

Another in vitro study found that grapeseed extract does not affect the activity of CYP1A2, CYP2C8, CYP2C19 and CYP2E1, and only moderately inhibits CYP2C9 and CYP2D6 at high concentrations of catechins. In addition, it has no significant effect on P-glycoprotein.

Grapeseed extracts appear to moderately inhibit the transporter protein OATP-B, but the clinical implications of this have not been established.

See under flavonoids, for information on the individual flavonoids present in grapeseed, and see under resveratrol, for the pharmacokinetics of resveratrol.

Interactions overview

Contrary to expectation, the concurrent use of grapeseed extracts and ascorbic acid may have detrimental cardiovascular effects. Evidence for other clinically relevant interactions appears to be generally lacking. For information on the interactions of flavonoids, see under flavonoids, and for the interactions of resveratrol, see under resveratrol.

Grapeseed + Ascorbic acid (Vitamin C)

The concurrent use of grapeseed and ascorbic acid (vitamin C) appears to increase systolic and diastolic blood pressure.

Clinical evidence

A placebo-controlled study in 69 hypertensive patients taking one or more antihypertensive medications investigated the effects on cardiovascular parameters of vitamin C 250 mg twice daily, grapeseed polyphenols 500 mg twice daily, or a combination of the two, for 6 weeks. There was a 3-week washout period between treatments. Vitamin C alone reduced systolic blood pressure by about 1.8mmHg, but the grapeseed polyphenols had no effect on blood pressure. However, treatment with the combination of vitamin C and polyphenols increased systolic blood pressure by 4.8 and 6.6mmHg and diastolic blood pressure by between 1.5 and 3.2mmHg. Endothelium-dependent and -independent vasodilatation, and markers of oxidative damage were not significantly altered.

Experimental evidence

No relevant data found.



Importance and management

Evidence is limited to one study, with no supporting mechanism to explain the effects seen, and so an interaction between vitamin C and grapeseed extract is not established. The authors of this study suggest that caution should be used when advising patients with hypertension on taking a combination of vitamin C and grapeseed. However, the general importance of any interaction is difficult to assess as the effect of taking these two supplements together is likely to vary depending on the patient and the degree to which their hypertension is controlled. It may be prudent to question a patient with poorly controlled blood pressure to establish if they are taking supplements containing both vitamin C and grapeseed, and discuss the option of stopping them to see if this improves their blood pressure control.

Grapeseed + Herbal medicines

No interactions found.

Grapeseed + Midazolam

The interaction between grapeseed and midazolam is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in rats, a single dose of an aqueous grapeseed extract had no significant effects on the pharmacokinetics of midazolam. However, after one week of treatment, grapeseed extract increased the elimination rate of midazolam by about 30%, and reduced its half-life by 28%. However, these effects were modest, and the AUC of midazolam was not significantly altered.


The study in rats suggests that grapeseed weakly induces the cytochrome P450 isoenzyme CYP3A4, the main route of midazolam metabolism. Some in vitro studies support this suggestion, although stronger effects may occur if the catechin content is high, see Pharmacokinetics.

Importance and management

Clinical evidence regarding an interaction between grapeseed and midazolam appears to be lacking. However, evidence from rat studies suggests that a clinically relevant interaction is unlikely and therefore no dose adjustments of midazolam are likely to be needed if grapeseed extract is also taken.