Herb-Drug Interactions: Ginkgo

2011

Contents

Ginkgo biloba L. (Ginkgoaceae)

Synonym(s) and related species

Fossil tree, Kew tree, Maidenhair tree.

Salisburia adiantifolia Sm., Salisburia biloba Hoffmanns.

Pharmacopoeias

Ginkgo (US Ph 32); Ginkgo capsules (US Ph 32); Ginkgo dry extract, refined and quantified (British Ph 2009, European Ph 2008); Ginkgo leaf (British Ph 2009, European Ph, 6th ed., 2008 and Supplements 6.1, 6.2, 6.3 and 6.4); Ginkgo tablets (US Ph 32); Powdered ginkgo extract (The United States Ph 32).

Constituents

Ginkgo leaves contain numerous flavonoids including the biflavone glycosides such as ginkgetin, isoginkgetin, bilobetin, sciadopitysin, and also some quercetin and kaempferol derivatives. Terpene lactones are the other major component, and these include ginkgolides A, B and C, and bilobalide, Ginkgo extracts may be standardised to contain between 22 and 27% flavonoids (flavone glycosides) and between 5 and 12% terpene lactones, both on the dried basis. The leaves contain only minor amounts of ginkgolic acids, and some pharmacopoeias specify a limit for these.

The seeds contain ginkgotoxin (4-O-methylpyridoxine) and ginkgolic acids.

Use and indications

The leaves of ginkgo are the part usually used. Ginkgo is often used to improve cognitive function in cases of dementia and memory loss, and it has been investigated for use in the treatment of Alzheimer’s disease. The ginkgolides are thought to possess antiplatelet and anti-inflammatory properties and it has been used for cerebrovascular and peripheral vascular disorders, tinnitus, asthma and to relieve the symptoms of altitude sickness.

Ginkgo seeds contain some toxic constituents; nevertheless, they are used in China and Japan, including as a food.

Pharmacokinetics

The two main active components of ginkgo are flavonoids and terpene lactones. For information on the pharmacokinetics of individual flavonoids present in ginkgo, see under flavonoids. In contrast to the flavonoids, the bioavailability of ginkgolide A and B (but not C) and bilobalide is relatively high and a large proportion of the dose is excreted unchanged in the urine.

The effects of ginkgo on cytochrome P450 isoenzymes appear to have been relatively well studied. It appears that the flavonoid fraction of ginkgo has more of an effect on the cytochrome P450 isoenzymes than the terpene lactones, and the effect on these enzymes can be halted relatively quickly when ginkgo is stopped.

In vitro and rat studies- have found that ginkgo may have some modest effects on CYP1A2 (see also theophylline). However, evidence from clinical studies using the specific probe substrate caffeine suggests that this is not clinically relevant with therapeutic doses of ginkgo. See Ginkgo + Caffeine.

Similarly, in vitro and rat studies have suggested that ginkgo affects CYP2C9, CYP2D6 and CYP1E2, but clinical studies using the specific probe substrates tolbutamide, for CYP2C9, dextromethorphan, for CYP2D6, and chlorzoxazone, for CYP1E2 have found no clinically relevant effect.

In contrast, in vitro findings suggesting that ginkgo may affect CYP3A4 and induce CYP2C9 are supported by clinical studies with midazolam and omeprazole, respectively. However, the effect of ginkgo on CYP3A4 is unclear (induction and inhibition reported), but any effect appears modest at best.

In vitro and rat studies. also suggest that ginkgo may affect CYP2B6 and CYP2C8, but the clinical relevance of this needs investigation.

Ginkgo is unlikely to affect the activity of P-glycoprotein to a clinically relevant extent (see digoxin).

Interactions overview

Ginkgo appears to decrease the levels of omeprazole; it seems likely that most other proton pump inhibitors will be similarly affected. Some evidence suggests that diltiazem and nifedipine levels may be raised by ginkgo, whereas nicardipine levels may be reduced.

Isolated cases of bleeding have been seen when ginkgo has been taken with conventional antiplatelet drugs, anticoagulants and NSAIDs, and some cases have occurred with ginkgo alone, although a clinically relevant antiplatelet effect for ginkgo alone is not established. Isolated case reports also suggest that ginkgo may cause seizures in patients taking phenytoin and/or valproate and one case had decreased phenytoin and valproate levels. Phenobarbital levels do not appear to be significantly affected, although this is based on experimental data only. Isolated cases also describe coma in a patient taking trazodone with ginkgo, priapism in a patient taking ginkgo with risperidone, and CNS depression in a patient taking ginkgo with valerian, although this case is confused by alcohol consumption.

There are some animal data suggesting that ciclosporin levels might be reduced by ginkgo, and it has been suggested that the extrapyramidal adverse effects of haloperidol and the ototoxic effects of amikacin may be enhanced by ginkgo.

Ginkgo does not appear to affect the pharmacokinetics/ metabolism of alprazolam, caffeine, chlorzoxazone, dextromethorphan, diclofenac, digoxin, donepezil, fexofenadine, flurbiprofen, lopinavir/ritonavir, midazolam, propranolol, theophylline, or tolbutamide to a clinically relevant extent.

For a case of anxiety and memory deficits in a woman taking several drugs and herbal medicines, including ginkgo. see St John’s wort + Buspirone.

For information on the interactions of individual flavonoids present in ginkgo, see under flavonoids.

Ginkgo + Aminoglycosides

The interaction between ginkgo and amikacin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

Ginkgo 100 mg/kg (EGb 761) daily for 20days and amikacin 600mg/kg daily for the first 14 days were given to rats. Amikacin-induced ototoxicity developed earlier and to a greater level than that caused by amikacin given alone. Ginkgo alone did not induce ototoxicity.

Mechanism

Unknown.

Importance and management

Ginkgo appears to accelerate the appearance of amikacin-induced ototoxicity and to increase its ototoxic effects in rats. Because the development of ototoxicity is cumulative, if ginkgo accelerates this process, there is potential for ototoxicity to develop at a lower cumulative dose. The available evidence is weak, but until more is known it may be prudent to carefully consider the risks and benefits of continuing ginkgo during treatment with drugs such as the aminoglycosides.

Ginkgo + Antiepileptics

Case reports describe seizures in three patients taking valproate, or valproate and phenytoin, when ginkgo was also taken.

Clinical evidence

A 55-year-old man taking valproate and phenytoin for a seizure disorder that developed following coronary artery bypass surgery suffered a fatal breakthrough seizure while swimming a year later. Analysis of his medical history showed that he had unexplained subtherapeutic serum levels of valproate and phenytoin on three occasions over the previous year. It was later found that the patient had also been taking numerous vitamins, supplements and herbal medicines without the knowledge of his physician, of which a ginkgo extract was stated to be the most common ingredient. The only other herbal medicines named in the report were ginseng and saw palmetto.

In another case, a 78-year-old man, whose epileptic seizures had been well controlled by valproate 1.2 g daily for 7 years, suffered a cluster of seizures after taking a ginkgo extract 120 mg daily for 2 weeks for the management of mild cognitive impairment. The ginkgo was stopped and the patient was reportedly seizure free 8 months later. All other medications taken by the patient remained unchanged.

An 84-year-old epileptic woman with severe dementia taking valproate 1.2 g daily had been seizure free for 2 years. After taking a ginkgo extract 120 mg daily for 12 days prescribed by her psychiatrist, she suffered a cluster of seizures, which were treated with intravenous diazepam in the accident and emergency department. The ginkgo extract was stopped on admission and the patient remained free of seizures 4 months later. All other medications taken by the patient were unchanged.

Experimental evidence

No relevant data found.

Mechanism

Unknown. Ginkgo seeds (nuts) contain the neurotoxin 4-0-methoxypyridoxine (ginkgotoxin), which indirectly inhibits the activity of glutamate decarboxylase, which in turn results in seizure induction by lowering the levels of gamma-aminobutyric acid (GABA). A large quantity of ginkgo nuts (about 70 to 80) alone have been reported to be the cause of seizures in a healthy 36-year-old woman. However, leaf extracts would not generally be expected to contain sufficient levels of this neurotoxin to be a problem.

Another possible mechanism is induction of the cytochrome P450 isoenzyme CYP2C19 by ginkgo. Phenytoin is a substrate of CYP2C19 and therefore, in theory, ginkgo may increase the metabolism of phenytoin and thereby reduce its levels. Ginkgo has been seen to induce CYP2C19 in clinical studies. See Ginkgo + Proton pump inhibitors.

Importance and management

Evidence for an interaction between ginkgo and valproate and phenytoin appears to be limited to case reports. The only case that measured serum levels of these antiepileptics is complicated by the use of numerous other supplements. An interaction is therefore by no means established. Nevertheless, it may be prudent to consider the possibility of reduced effects if a patient taking phenytoin and/or valproate wishes also to take ginkgo.

For details of a possible interaction between ginkgo and phenobarbital in animals see Ginkgo + Phenobarbital.

Ginkgo + Antiplatelet drugs

Ginkgo biloba has been associated with platelet, bleeding and clotting disorders, and there are isolated reports of serious adverse reactions after its concurrent use with antiplatelet drugs such as aspirin, clopidogrel and ticlopidine.

Clinical evidence

A study in 10 healthy subjects found no significant increase in the antiplatelet effects of single doses of clopidogrel 75 mg or cilostazol 100 mg when a single dose of ginkgo 120 mg was added. However, the bleeding time was significantly increased when cilostazol was combined with ginkgo, although none of the subjects developed any significant adverse effects. Another study in 8 healthy subjects found that ginkgo 40 mg three times daily had no significant effect on the pharmacokinetics of a single 250-mg dose of ticlopidine taken on day 4.

A randomised, double-blind study in 55 patients with established peripheral artery disease (PAD), or with risk factors for developing PAD, found that the addition of ginkgo 300 mg (standardised extract EGb 761) in divided doses to aspirin 325 mg daily did not have a significant effect on platelet aggregation. Five of the patients taking combined therapy reported nosebleeds or minor bleeding; however, 4 patients from the aspirin-only group also reported minor bleeding. Similarly, a study in 41 healthy subjects found that 120-mg ginkgo-coated tablets (EGb 761) twice daily had no effect on the antiplatelet activity of aspirin 500 mg daily given for 7 days. Minor bleeding was seen in a few subjects but this was attributed to the use of aspirin. In an analysis of supplement use, 23% of 123 patients were currently taking supplements, and 4 patients were found to be taking ginkgo and aspirin. However, no problems from this use were found on review of the patients’ notes.

Nevertheless, a number of cases of clinically significant bleeding have been reported. A 70-year-old man developed spontaneous bleeding from the iris into the anterior chamber of his eye within one week of starting to take a ginkgo supplement (Ginkoba) tablet twice daily. He experienced recurrent episodes of blurred vision in one eye lasting about 15 minutes, during which he could see a red discoloration through his cornea. Each tablet contained 40 mg of concentrated (50:1) extract of ginkgo. He was also taking aspirin 325 mg daily, which he had taken uneventfully for 3 years since having coronary bypass surgery. He stopped taking the ginkgo but continued with the aspirin, and 3 months later had experienced no recurrence of the bleeding. Another case reports persistent postoperative bleeding from a hip arthroplasty wound, which continued despite stopping aspirin. On closer questioning, the patient had continued to take ginkgo extract 120 mg daily postoperatively. The oozing from the wound gradually reduced when the ginkgo was stopped.

A search of Health Canada’s database of spontaneous adverse reactions for the period January 1999 to June 2003 found 21 reports of suspected adverse reactions associated with ginkgo. Most of these involved platelet, bleeding and clotting disorders. One report of a fatal gastrointestinal haemorrhage was associated with ticlopidine and ginkgo, both taken over 2 years along with other medications. Another report was of a stroke in a patient taking multiple drugs, including clopidogrel, aspirin and a herbal product containing ginkgo.

Experimental evidence

Ginkgo (EGb 761) 40mg/kg daily had no effect on the antiplatelet activity of ticlopidine 50 mg/kg daily when given to rats for 3 days. However, when both were given for 5 days, the inhibition of platelet aggregation was double that of ticlopidine given alone and the bleeding time was increased by about 60%. Also, when given for 9 days, the combination was twice as effective at inhibiting thrombus formation when compared with the same dose of ticlopidine alone.

Mechanism

The reason for the bleeding is not known, but ginkgo extract contains ginkgolide B, which is a potent inhibitor of platelet-activating factor in vitro; this is needed for arachidonate-independent platelet aggregation. However, in one controlled study in healthy subjects, taking a ginkgo preparation alone for 2 weeks had no effect on platelet function. Nevertheless, there are case reports of ginkgo supplements, on their own, being associated with prolonged bleeding times, left and bilateral subdural haematomas, a right parietal haematoma, a retrobulbar haemorrhage, post-laparoscopic cholecystectomy bleeding and subarachnoid haemorrhage. It seems that the effects of ginkgo and conventional antiplatelet drugs can be additive, leading to bleeding complications on rare occasions.

Importance and management

The evidence from these case reports is too slim to advise patients taking aspirin, clopidogrel or ticlopidine to avoid ginkgo, but some do recommend caution, which seems prudent, especially as this is generally advised with most combinations of conventional antiplatelet drugs. There may also be a theoretical risk of increased bleeding if ginkgo is taken with other antiplatelet drugs and anticoagulants; interactions have been reported with NSAIDs, some of which have antiplatelet effects, and with warfarin.

Consider also Ginkgo + NSAIDs and Ginkgo + Warfarin and related drugs.

Ginkgo + Benzodiazepines

Ginkgo does not significantly affect the pharmacokinetics of alprazolam. Studies with midazolam suggest that ginkgo may increase, decrease or have no effect on its metabolism.

Clinical evidence

(a) Alprazolam

Ginkgo leaf extract 120mg twice daily for 16 days was given to 12 healthy subjects before and with a single 2-mg dose of alprazolam on day 14. The ginkgo preparation (Ginkgold) was standardised to ginkgo flavonol glycosides 24% and terpene lactones 6%. The alprazolam AUC was reduced by 17%, and the maximum concentration was not significantly affected.

(b) Midazolam

In 12 healthy subjects, ginkgo 60 mg four times daily for 28 days did not affect the metabolism of midazolam 8 mg. The ginkgo preparation used was stated to contain 24% flavone glycosides and 6% terpene lactones. These findings were repeated in a later study using the same criteria in 12 elderly healthy subjects. In contrast, in another similar study, ginkgo 120 mg twice daily modestly reduced the AUC and maximum serum levels of a single 8-mg dose of midazolam by about one-third. The ginkgo preparation was assayed, and contained 29% flavonol glycosides and 5% terpene lactones. Furthermore, in yet another study in 10 healthy subjects, ginkgo 360 mg daily for 28 days increased the AUC of a single 8-mg dose of oral midazolam by about one-quarter. The ginkgo preparation used was Ginkgold, which was stated to contain 24% flavone glycosides and 6% terpene lactones.

Experimental evidence

In an experimental study, unfamiliar pairs of rats were placed together in a novel arena for 10 minutes to determine the effects of combined administration of ginkgo and diazepam on social behaviour. Social contact between rats given ginkgo 96 mg/kg (EGb 761) daily for 8 days and then a single injection of diazepam 1 mg/kg 30 minutes before testing, was significantly higher than those given ginkgo or diazepam alone.

Mechanism

Alprazolam and midazolam are probe substrates for the cytochrome P450 isoenzyme CYP3A4. The studies here show that ginkgo has minimal effects on this isoenzyme, the maximum effect on midazolam being about a 33% reduction in AUC. However, it is unusual for studies to show opposite effects (one of the studies found a minor increase in midazolam AUC), and the reasons for this are unclear, but may be to do with the methodology (use of midazolam metabolic ratios rather than midazolam exposure, and length of sampling time and the fact that in one study the subjects had previously received lopinavir/ritonavir for 30 days, concurrently with the ginkgo for 2 weeks, just 2 weeks before the midazolam).

The reasons for the experimental findings are not understood but ginkgo may interact with diazepam through its effects on the gamma-aminobutyric acid (GABA) receptor.

Importance and management

The pharmacokinetic evidence here shows that alprazolam and midazolam levels are not significantly affected by ginkgo, and no clinically relevant interaction would be expected. The conflicting finding of the metabolism of midazolam being slightly inhibited in one study and slightly induced in another is, however, unexplained, but either effect would be modest at the most. Alprazolam and midazolam are used as a probe drugs for CYP3A4 activity, and therefore these results also suggest that a clinically relevant pharmacokinetic interaction as a result of this mechanism between ginkgo and other CYP3A4 substrates is unlikely.

The clinical relevance of the possible interaction of ginkgo with diazepam in rats is unknown.

Ginkgo + Buspirone

For a case of anxiety, with episodes of over-sleeping and memory deficits in a woman taking fluoxetine and buspirone with St John’s wort, ginkgo and melatonin, see St John’s wort + Buspirone.

Ginkgo + Caffeine

Ginkgo does not appear to affect the pharmacokinetics of caffeine.

Clinical evidence

In 12 healthy subjects, ginkgo 60 mg four times daily for 28 days did not affect the metabolism of caffeine 100 mg. The ginkgo preparation used was standardised to 24% flavone glycosides and 6% terpene lactones. These findings were repeated in a later study using the same criteria in 12 elderly healthy subjects.

Experimental evidence

No relevant data found.

Mechanism

This study shows that ginkgo has no clinically relevant effect on the cytochrome P450 isoenzyme CYP1A2.

Importance and management

Evidence from studies in healthy subjects suggests that ginkgo does not affect the metabolism of caffeine and is therefore unlikely to increase its adverse effects. Caffeine is used as a probe drug for CYP1A2 activity, and therefore these results also suggest that a pharmacokinetic interaction as a result of this mechanism between ginkgo and other CYP1A2 substrates is unlikely.

Ginkgo + Calcium-channel blockers; Diltiazem

The interaction between ginkgo and diltiazem is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

Ginkgo 20 mg/kg approximately doubled the AUC and maximum serum levels of oral diltiazem 30 mg/kg when given to rats 1 hour before diltiazem. Ginkgo 20 mg/kg had no significant effect on the levels of intravenous diltiazem 3 mg/kg.

Mechanism

The authors suggest that ginkgo may inhibit the activity of the cytochrome P450 isoenzyme CYP3A4 or P-glycoprotein, both of which would raise diltiazem levels by inhibiting its metabolism or increasing its absorption, respectively. However, in clinical studies, ginkgo had no clinically relevant effect on the P-glycoprotein substrate digoxin, or on the conventional CYP3A4 probe substrate, midazolam.

Importance and management

An interaction between ginkgo and diltiazem has only been demonstrated in one study in rats, and ginkgo does not appear to have clinically relevant effects on the activity of P-glycoprotein or on the metabolism of other CYP3A4 substrates such as the benzodiazepines. Because the findings of animal studies cannot be directly extrapolated to humans, further study is needed before any specific recommendations can be made. Until more is known, bear the possibility of an interaction in mind in the event of an unexpected response to treatment.

Ginkgo + Calcium-channel blockers; Nicardipine

The interaction between ginkgo and nicardipine is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In an experimental study in rats, ginkgo extract 0.5% daily for 4 weeks significantly reduced the hypotensive effects of both oral nicardipine 30 mg/kg and intravenous nicardipine 30 micrograms/ kg. These findings were repeated in a later study in rats: ginkgo extract 0.5% daily for 2 weeks reduced the maximum serum levels and AUC of oral nicardipine 30 mg/kg by about 65%. The ginkgo extract contained 24% flavonoids (12% quercetin) and 9% terpene lactones.

Mechanism

The authors suggested that ginkgo may induce the cytochrome P450 subfamily CYP3A, which would increase the metabolism of nicardipine, a CYP3A4 substrate, and reduce its levels. However, in contrast, studies with diltiazem and nifedipine, below have shown inhibition of CYP3A4 and increased levels. Moreover, note also that clinically relevant CYP3A4 inhibition has not been see with the conventional CYP3A4 probe substrate, midazolam.

Importance and management

These experiments in rats suggest that ginkgo can significantly reduce the levels of nicardipine by inducing CYP3A, but note that there is experimental evidence of ginkgo increasing nifedipine and diltiazem levels. Moreover, clinical studies with CYP3A4 substrates such as the benzodiazepines, have not shown any clinically relevant pharmacokinetic interaction. Because of this, and because the doses used were higher than those used in humans, the animal data here are unlikely to be of general clinical importance.

Ginkgo + Calcium-channel blockers; Nifedipine

Ginkgo may increase the levels and some of the effects of nifedipine.

Clinical evidence

In the preliminary report of a clinical study, 22 healthy subjects were given ginkgo 120mg daily for 18 days before a single 10-mg oral dose of nifedipine. Ginkgo increased the levels of nifedipine by about 50%.

In another study, a single 240-mg dose of ginkgo extract did not significantly affect the pharmacokinetics of a single 10-mg oral dose of nifedipine when they were given at the same time to 8 healthy subjects. However, the maximum level tended to increase (30% increase), and two subjects experienced a doubling of nifedipine maximum serum levels. In addition, the incidence and severity of headaches, hot flushes and dizziness tended to be higher with the combination when compared with nifedipine alone. Subjects also experienced increased heart rate with the combination although the decrease in blood pressure was unaffected. The ginkgo extract used in this study contained 24% flavonoids and 6% terpene lactones.

Experimental evidence

In a study in rats, ginkgo extract 20 mg/kg increased the maximum serum levels and AUC of an oral dose of nifedipine 5 mg/kg by about 60% when they were given at the same time. Ginkgo extract had no effect on the pharmacokinetics of intravenous nifedipine.

Mechanism

Experimental data have found that ginkgo has no significant effect on the pharmacokinetics of intravenous nifedipine, suggesting that ginkgo reduces the first-pass metabolism of nifedipine. Ginkgo may therefore inhibit the cytochrome P450 isoenzyme CYP3A4, which would reduce the pre-systemic metabolism of nifedipine, a CYP3A4 substrate, and increase its levels. Note that simultaneous administration of single doses is probably insufficient to completely evaluate CYP3A4 inhibition. Note also that clinically relevant CYP3A4 inhibition has not been seen with the conventional CYP3A4 probe substrates such as midazolam. See Ginkgo + Benzodiazepines.

Importance and management

Limited clinical data suggest that ginkgo may raise the levels of nifedipine and increase its effects. Until more is known, some caution might be warranted when they are used together. Monitor for signs of nifedipine adverse effects such as headaches, hot flushes, dizziness and palpitations. If they become apparent, advise the patient to stop taking ginkgo.

Ginkgo + Chlorzoxazone

Ginkgo does not appear to affect the pharmacokinetics of chlorzoxazone.

Evidence, mechanism, importance and management

In a study in 12 healthy subjects, ginkgo 60 mg four times daily for 28 days did not significantly affect the metabolism of chlorzoxazone 500 mg. The ginkgo preparation used was standardised to 24% flavone glycosides and 6% terpene lactones. These findings were repeated in a later study using the same criteria in 12 elderly healthy subjects.

Chlorzoxazone is used a probe substrate for the cytochrome P450 isoenzyme CYP2E1, and this study shows that ginkgo has no clinically relevant effect on this isoenzyme. No action is necessary with combined use, and no pharmacokinetic interaction would be expected with other substrates of CYP2E1.

Ginkgo + Ciclosporin

The interaction between ginkgo and ciclosporin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In a study in rats, ginkgo extract 8 mL/kg (containing the flavonoid quercetin 775 nanomol/kg) reduced the maximum serum levels and AUC of oral ciclosporin by about 60% and 50% respectively, but had no effect on the pharmacokinetics of intravenous ciclosporin.

Mechanism

The authors suggest that the flavonoid component of ginkgo, quercetin, might affect ciclosporin levels via its effects on P-glycoprotein or cytochrome P450 isoenzyme CYP3A4. However, in clinical studies, ginkgo had no clinically relevant effect on the P-glycoprotein substrate digoxin, or on midazolam, a CYP3A4 substrate.

Importance and management

The evidence for an interaction between ginkgo and ciclosporin is limited to one study in rats. However, ginkgo contains fiavonoids, and of these quercetin has been implicated in modest interactions with ciclosporin in other studies (see Fiavonoids + Ciclosporin for more information). On this basis, while there is insufficient evidence to suggest that concurrent use should be avoided, there is the possibility that ginkgo may make ciclosporin levels less stable as the quercetin content of different preparations is likely to vary. Some caution might therefore be prudent on concurrent use.

Ginkgo + Dextromethorphan

Ginkgo does not appear to affect the metabolism of dextromethorphan.

Clinical evidence

Ginkgo leaf extract 120 mg twice daily for 16 days was given to 12 healthy subjects with a single 30-mg dose of dextromethorphan on day 14. The ginkgo preparation (Ginkgold) contained ginkgo flavonol glycosides 24% and terpene lactones 6%. There was no change in the metabolism of dextromethorphan when it was taken after the ginkgo.

In 12 healthy subjects, ginkgo 60 mg four times daily for 28 days did not significantly affect the metabolism of debrisoquine 5 mg. The ginkgo preparation used was standardised to 24% flavone glycosides and 6% terpene lactones. These findings were repeated in a later study using the same criteria in 12 elderly healthy subjects.

Experimental evidence

In in vitro experiments, low-dose and high-dose ginkgo modestly decreased and increased the metabolism of dextromethorphan, respectively.

Mechanism

Dextromethorphan is used as a probe substrate for the cytochrome P450 isoenzyme CYP2D6, and the study shows that ginkgo has no clinically relevant effect on this isoenzyme. Studies with debrisoquine, another CYP2D6 substrate, also suggest that ginkgo does not affect CYP2D6.

Importance and management

The available evidence seems to reliably suggest that ginkgo does not affect the pharmacokinetics of dextromethorphan. No action is therefore needed on concurrent use.

Dextromethorphan is used as a probe drug for CYP2D6 activity, and therefore these results (along with those for debrisoquine) also suggest that a clinically relevant pharmacokinetic interaction between ginkgo and other CYP2D6 substrates is unlikely.

Ginkgo + Digoxin

Ginkgo does not appear to affect the pharmacokinetics of digoxin.

Clinical evidence

A study in 8 healthy subjects found that ginkgo leaf extract 80 mg three times daily had no significant effects on the pharmacokinetics of a single 500-microgram dose of digoxin.

Experimental evidence

In in vitro experiments, ginkgo modestly inhibited the cellular transport of digoxin resulting in the intracellular accumulation of digoxin.

Mechanism

Digoxin is a P-glycoprotein substrate and in vitro studies suggest that ginkgo may inhibit the activity of this drug transporter protein, which could lead to increased digoxin levels. However, this effect was not seen clinically.

Importance and management

The clinical study suggests that ginkgo is unlikely to alter digoxin levels in clinical use. Therefore no dosage adjustment would be expected to be necessary if patients taking digoxin also wish to take ginkgo. As digoxin is used as a probe substrate for P-glycoprotein, this study also suggests that ginkgo is unlikely to interact with other drugs that are substrates of P-glycoprotein. No action is necessary with combined use.

Ginkgo + Donepezil

Ginkgo does not appear to alter the pharmacokinetics or effects of donepezil.

Evidence, mechanism, importance and management

In a pharmacokinetic study, 14 elderly patients with Alzheimer’s disease were given donepezil 5 mg daily for at least 20 weeks, after which ginkgo extract 90 mg daily was also given for a further 30 days. Concurrent use did not affect the pharmacokinetics or cholinesterase activity of donepezil, and cognitive function appeared to be unchanged. Therefore, over the course of 30 days, concurrent use appears neither beneficial nor detrimental. No action is necessary with combined use.

Ginkgo + Fexofenadine

Ginkgo does not appear to affect the pharmacokinetics of fexofenadine.

Evidence, mechanism, importance and management

In a clinical study, 13 healthy subjects took a single oral dose of fexofenadine 120 mg after 4 weeks of twice-daily doses of ginkgo 120 mg containing 29% flavonol glycosides and 5% terpene lactones. The pharmacokinetics of fexofenadine were not significantly affected.

Fexofenadine is a P-glycoprotein substrate and the findings of this study therefore suggest that ginkgo does not affect P-glycoprotein activity. No action is necessary with combined use.

Ginkgo + Food

No interactions found.

Ginkgo + Haloperidol

Animal studies suggest that ginkgo may increase extrapyramidal effects in response to haloperidol, but clinical studies do not appear to have reported this effect.

Clinical evidence

Ginkgo has been tried in schizophrenia as an addition to standard antipsychotics such as haloperidol. For example, in one clinical study, an improvement in positive symptoms was seen in 43 schizophrenic patients given ginkgo extract 360 mg daily with haloperidol 250 micrograms/kg daily for 12 weeks. This study did not report any adverse events.

Experimental evidence

High-dose ginkgo extract (EGb 761, TeboninĀ®), 80mg/kg daily for 5 days, significantly potentiated the cataleptic adverse effects of haloperidol 2mg/kg given to rats on the first and last day. The cataleptic response to haloperidol is used as an animal model of extrapyramidal adverse effects.

Mechanism

Unknown. Haloperidol is a dopamine D2-receptor antagonist. It is thought that ginkgo may interfere with dopamine neurotransmission by scavenging nitric oxide, which in turn reduces locomotor activity.

Importance and management

The authors of the experimental study caution that there is a possibility of an increase in extrapyramidal effects when ginkgo is used with haloperidol. However, their study in rats used high doses, and there are clinical studies investigating the addition of ginkgo to haloperidol that do not mention this adverse effect. Nevertheless, a clinical study specifically of extrapyramidal effects would be required to investigate this further. It may be prudent to be aware of this possible interaction in case there is an unexpected outcome in patients taking haloperidol and ginkgo.

Ginkgo + Herbal medicines; Valerian

A case report describes psychotic symptoms in a woman who took ginkgo with valerian, but an interaction was not established as the cause.

Clinical evidence

A 51-year-old woman taking valerian 1 to 2 g daily and an unknown amount of ginkgo daily, and who regularly consumed over 1 L of wine daily, was admitted to hospital after a fainting episode and changes in mental status. Over the next couple of days she exhibited a variety of psychotic symptoms including paranoid delusions, disorganised behaviour, anxiety and auditory hallucinations. Her blood-alcohol level was zero on admission and there was no evidence of alcohol withdrawal during her stay in hospital.

Experimental evidence

No relevant data found.

Mechanism

Unclear. Valerian has been associated with CNS depressant effects when given alone and ginkgo is used primarily to improve cognitive function and memory loss. Alcohol, valerian and ginkgo were also all being withdrawn at the same time. These factors make it difficult to find the exact cause of the psychotic symptoms.

Importance and management

This appears to be the only case report in the literature and, because of the multiple factors involved, such as a history of alcohol abuse, it is difficult to assess its general importance. Bear this interaction in mind in case of an adverse response to the combination of ginkgo and valerian.

Ginkgo + NSAIDs

An isolated case describes fatal intracerebral bleeding in a patient taking ginkgo with ibuprofen, and another case describes prolonged bleeding and subdural haematomas in another patient taking gingko and rofecoxib. Studies with diclofenac and flurbiprofen showed that ginkgo had no effect on the pharmacokinetics of these drugs.

Clinical evidence

A case of fatal intracerebral bleeding has been reported in a 71-year-old patient taking a ginkgo supplement (Gingium) 4 weeks after he started to take ibuprofen 600 mg daily. A 69-year-old man taking a ginkgo supplement and rofecoxib had a subdural haematoma after a head injury, then recurrent small spontaneous haematomas. He was subsequently found to have a prolonged bleeding time, which returned to normal 1 week after stopping the ginkgo supplement and rofecoxib, and remained normal after restarting low-dose rofecoxib.

A placebo-controlled study in 11 healthy subjects who were given ginkgo leaf (Ginkgold) 120 mg twice daily for three doses, followed by a single 100-mg dose of flurbiprofen, found that the pharmacokinetics of flurbiprofen were unchanged.

A study in 12 healthy subjects who were given diclofenac 50 mg twice daily for 14 days, with ginkgo extract (Ginkgold) 120 mg twice daily on days 8 to 15, found no alteration in the AUC or oral clearance of diclofenac.

Experimental evidence

See Mechanism, below.

Mechanism

The reason for the bleeding is not known, but ginkgo extract contains ginkgolide B, which is a potent inhibitor of platelet-activating factor in vitro, which is needed for arachidonate-independent platelet aggregation. However, in one controlled study in healthy subjects, taking a ginkgo preparation alone for 2 weeks had no effect on platelet function. Nevertheless, there are case reports of ginkgo supplements, on their own, being associated with prolonged bleeding times, left and bilateral subdural haematomas, a right parietal haematoma, a retrobulbar haemorrhage,post-laparoscopic cholecystectomy bleeding and subarachnoid haemorrhage. Ibuprofen is an inhibitor of platelet aggregation, but selective inhibitors of COX-2 such as rofecoxib have no effect on platelets and would not be expected to potentiate any bleeding effect of ginkgo.

The pharmacokinetic studies involving diclofenac and flurbipro-fen were designed to identify whether ginkgo exerted an inhibitory effect on cytochrome P450 isoenzyme CYP2C9, and confirm that ginkgo has no effect on this isoenzyme.

Importance and management

The evidence from these reports is too slim to forbid patients to take NSAIDs and ginkgo concurrently, but some do recommend caution. Medical professionals should be aware of the possibility of increased bleeding tendency with ginkgo, and report any suspected cases.

For other reports of bleeding events with ginkgo see Ginkgo + Antiplatelet drugs, and Ginkgo + Warfarin and related drugs.

Ginkgo + Phenobarbital

The interaction between ginkgo and phenobarbital is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In an experimental study in rats, ginkgo extract 0.5% daily (equating to about 1.3 g/kg) for 2 weeks modestly reduced the maximum serum levels of a single 90-mg/kg dose of phenobarbital by about 35%, and reduced the AUC by about 18% (not statistically significant). Conversely, the phenobarbital-induced sleeping time was reduced markedly from about 8 hours to about 3 hours. The ginkgo extract used was standardised to 24% flavonoids and 9% terpenes.

Mechanism

Ginkgo may induce the cytochrome P450 isoenzyme CYP2B subfamily, which would increase the metabolism of phenobarbital, a CYP2B6 substrate, and reduce its levels. However, the modest reduction in levels seen with high-dose ginkgo does not explain the marked reduction in sleeping time.

Importance and management

The evidence for this interaction is limited to an animal study and the doses used are far higher than those used in humans. It is therefore difficult to assess the clinical relevance of this interaction. If anything, it would appear that the interaction may be beneficial (reduced sedation), but this is far from established.

For details of possible interactions with other antiepileptics, see Ginkgo + Antiepileptics.

Ginkgo + Propranolol

The interaction between ginkgo and propranolol is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

The maximum serum levels and AUC of propranolol 10 mg/kg given to rats, pretreated with ginkgo extract 100 mg/kg (EGb 761) for 10 days, were reduced by about 40% and 45% respectively when compared with propranolol alone. The serum levels and AUC of its metabolite, N-desisopropylpropranolol, were increased by about 70% and 55%. Ginkgo extract 10 mg/kg had no effect.

Mechanism

The authors suggested that ginkgo may induce the activity of the cytochrome P450 isoenzyme CYP1A2, which is one of the major enzymes involved in the metabolism of propranolol. Ginkgo would therefore reduce the levels of propranolol by inducing its metabolism. However, compare caffeine.

Importance and management

This experiment in rats suggests that high-dose ginkgo might significantly reduce the levels of propranolol by inducing CYP1A2. However, a human study using caffeine as a CYP1A2 probe substrate found that ginkgo does not affect CYP1A2 to a clinically relevant extent (see Ginkgo + Caffeine). Therefore an interaction with propranolol based on this mechanism is unlikely to be clinically important.

Ginkgo + Protease inhibitors

Ginkgo does not appear to affect the pharmacokinetics of lopinavir/ritonavir.

Clinical evidence

In a study in 14 healthy subjects, ginkgo 120 mg twice daily for 2 weeks had no significant effect on the pharmacokinetics of lopinavir/ritonavir 400mg/100mg twice daily (given for 2 weeks alone before adding the ginkgo). The ginkgo extract was assayed and contained 29% flavonol glycosides and 5% terpene lactones.

Experimental evidence

No relevant data found.

Mechanism

The authors suggest that, without ritonavir, the levels of lopinavir would have been reduced by ginkgo because they also found that ginkgo modestly reduced the levels of midazolam, probably by inducing the cytochrome P450 isoenzyme CYP3A4. As ritonavir is an inhibitor of CYP3A4, they suggest that it attenuates the action of ginkgo on lopinavir metabolism. However, note that all protease inhibitors are inhibitors of CYP3A4 to varying extents, and note also that, in other studies with midazolam, ginkgo had no effect on midazolam levels, or even caused a minor increase in levels, which suggests that ginkgo does not have a clinically relevant effect on CYP3A4 activity. Consider also Ginkgo + Benzodiazepines.

Importance and management

The study here shows that ginkgo does not alter the pharmacokinetics of lopinavir/ritonavir, and no special precautions are required on concurrent use. This would apply to all other ritonavir-boosted protease inhibitors. As regards protease inhibitors that are not boosted by ritonavir, the authors of this study recommend avoiding ginkgo. This seems an over-cautious approach, given that the sum of studies available shows that ginkgo does not have a clinically relevant effect on the probe CYP3A4 substrate midazolam.

Ginkgo + Proton pump inhibitors

Ginkgo induces the metabolism of omeprazole. Most other proton pump inhibitors are likely to be similarly affected.

Clinical evidence

In one study, 18 healthy Chinese subjects were given a single 40-mg dose of omeprazole before and after a 12-day course of a standardised extract of ginkgo 140 mg twice daily. The subjects were divided into three groups: homozygous extensive CYP2C19 metabolisers (6 subjects), heterozygous extensive CYP2C19 metabolisers (5) and poor CYP2C19 metabolisers (7). The AUC of omeprazole was modestly decreased by 42%, 27% and 40%, respectively, and the plasma levels of the inactive metabolite, hydroxyomeprazole, were increased by 38%, 100% and 232% in the three groups, respectively. Renal clearance of hydroxyomeprazole was also reduced by ginkgo.

Experimental evidence

No relevant data found.

Mechanism

It was concluded that ginkgo increases the metabolism (hydroxylation) of omeprazole by inducing the cytochrome P450 isoenzyme CYP2C19.

Importance and management

This appears to be the only study examining the effects of ginkgo on proton pump inhibitors. However, the reduction seen in the AUC of omeprazole (about 40%) suggests that there is a possibility that omeprazole will be less effective in patients taking ginkgo. As all PPIs are metabolised by CYP2C19 to varying extents, it is likely that the effects of ginkgo seen in these studies will be similar with other PPIs, although note that rabeprazole is much less dependent on this route of metabolism than other PPIs.

There is insufficient evidence to generally recommend that ginkgo should be avoided in patients taking PPIs. However, the potential reduction in the efficacy of the PPI should be borne in mind, particular where the consequences may be serious, such as in patients with healing ulcers.

Ginkgo + Risperidone

An isolated case describes priapism in a patient taking risperidone and ginkgo.

Clinical evidence

A 26-year-old paranoid schizophrenic who had been taking risperidone 3 mg daily for the past 3 years developed priapism that had lasted for 4 hours 2 weeks after starting ginkgo 160 mg daily for occasional tinnitus. The priapism required treatment, and both ginkgo and risperidone were stopped. Risperidone was then restarted and the patient reported no further episodes of priapism at follow-up 6 months later.

Experimental evidence

No relevant data found.

Mechanism

Unclear. Risperidone alone does rarely cause priapism, probably because of its alpha-adrenergic properties, and ginkgo might have vascular effects that could be additive. Ginkgo is unlikely to inhibit the metabolism of risperidone by inhibiting the cytochrome P450 isoenzyme CYP2D6 because it has no clinical effect on other CYP2D6 substrates. See Ginkgo + Dextromethorphan.

Importance and management

The use of ginkgo is widespread and this appears to be the only report in the literature of an interaction with risperidone. Its general relevance is therefore unclear. Bear it in mind in the event of an unexpected response to treatment.

Ginkgo + Theophylline

The interaction between ginkgo and theophylline is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In an experimental study in rats pretreated with oral ginkgo extract 100 mg/kg daily for 5 days, the serum levels and AUC of a single 10 mg/kg oral dose of theophylline given on day 6 were reduced by about 20% and 40%, respectively. The clearance was increased by 70%. A less marked effect was seen with ginkgo 10 mg/kg (30% increase in clearance). Similar results were seen with intravenous theophylline 10 mg/kg.

Mechanism

This interaction is thought to be due to the induction of the cytochrome P450 isoenzyme CYP1A2 by ginkgo. Theophylline is a substrate of CYP1A2 and by inducing the activity of this isoenzyme, theophylline is more readily metabolised and cleared from the body. However, ginkgo had no relevant effect on another CYP1A2 substrate, caffeine, in humans. See Ginkgo + Caffeine.

Importance and management

The evidence for this interaction is limited to experimental data and the dose of ginkgo used is far higher than the most common clinical dose. A human study using caffeine as a CYP1A2 probe substrate, found that ginkgo does not affect CYP1A2 to a clinically relevant extent. Therefore an interaction with theophylline based on this mechanism is unlikely to be clinically important.

Ginkgo + Tolbutamide

Gingko does not appear to have a clinically relevant effect on the metabolism or blood-glucose-lowering effects of tolbutamide.

Clinical evidence

In healthy subjects, ginkgo extract (Ginkgold) 120 mg twice daily for 7 days had no effect on the urinary metabolic ratio of tolbutamide.In another study in 10 healthy subjects, ginkgo 360 mg daily for 28 days slightly reduced the AUC of a single 125-mg oral dose of tolbutamide by about 16%, with no significant changes in other pharmacokinetic parameters. The ginkgo product used was Ginkgold, which contained 24% flavone glyco sides and 6% terpene lactones. The pharmacodynamics of tolbutamide were not significantly altered although there was a tendency towards the attenuation of its hypoglycaemic effects by ginkgo (14% reduction).

Experimental evidence

In an experimental study, ginkgo 32 mg/kg given daily for 5 days before a single 40-mg/kg dose of tolbutamide significantly reduced its blood-glucose-lowering effects in aged rats. However, when a single 100-mg/kg dose of ginkgo was given with a single 40-mg/kg dose of tolbutamide, the blood-glucose levels were significantly lower, when compared with tolbutamide alone, suggesting that ginkgo potentiated the blood-glucose-lowering effects of tolbutamide.

Mechanism

It was suggested that ginkgo might induce the cytochrome P450 isoenzyme CYP2C9, by which tolbutamide is metabolised. However, the clinical study shows that ginkgo has little or no clinically relevant effect on CYP2C9. The disparate effects between single and multiple dose administration in the animal study are not understood.

Importance and management

From the clinical evidence, it is clear that ginkgo has little, if any, effect on the metabolism and blood-glucose-lowering effects of tolbutamide. A clinically relevant interaction therefore seems unlikely.

Tolbutamide is used as a probe drug for CYP2C9 activity, and therefore these results also suggest that a clinically relevant pharmacokinetic interaction between ginkgo and other CYP2C9 substrates is unlikely.

Ginkgo + Trazodone

Coma developed in an elderly patient with Alzheimer’s disease after she took trazodone and ginkgo.

Clinical evidence

An 80-year-old woman with Alzheimer’s disease became comatose a few days after starting to take low-dose trazodone 20 mg twice daily and ginkgo. The patient woke immediately after being given flumazenil 1 mg intravenously.

Experimental evidence

No relevant data found.

Mechanism

It was suggested that the flavonoids in the ginkgo had a subclinical direct effect on the benzodiazepine receptor. In addition, it was suggested that ginkgo increased the metabolism of trazodone to its active metabolite, 1-(m-chlorophenyl) piperazine (mCPP) by the cytochrome P450 isoenzyme CYP3A4. The increased levels of the metabolite were thought to have enhanced the release of GABA (gamma-aminobutyric acid). Flumazenil may have blocked the direct effect of the flavonoids, thus causing the GABA activity to fall below the level required to have a clinical effect. However, note that clinically relevant CYP3A4 induction has not been seen with the conventional CYP3A4 probe substrate midazolam. See Ginkgo + Benzodiazepines.

Importance and management

Evidence for an interaction between ginkgo and trazodone appears to be limited to this isolated case, from which no general conclusions can be drawn. Bear this interaction in mind in case of an unexpected response to concurrent use.

Ginkgo + Warfarin and related drugs

Evidence from pharmacological studies in patients and healthy subjects suggests that ginkgo does not usually interact with warfarin. However, an isolated report describes intracerebral haemorrhage associated with the use of ginkgo and warfarin, and there are a few reports of bleeding associated with the use of ginkgo alone.

Clinical evidence

In a randomised, crossover study in 21 patients stabilised on warfarin, ginkgo extract 100 mg daily (Bio-Biloba) for 4 weeks did not alter the INR or the required dose of warfarin, when compared with placebo. Similarly, in another study in healthy subjects, Tavonin (containing standardised dry extract EGb 761 of ginkgo equivalent to 2 g of leaf) two tablets three times daily for 2 weeks did not affect either the pharmacokinetics or pharmacodynamics (INR) of a single dose of warfarin given on day 7. Moreover, a retrospective review of 21 clinical cases involving the concurrent use of ginkgo and warfarin also found no evidence of altered INRs. Conversely, a report describes an intracerebral haemorrhage, which occurred in an elderly woman within 2 months of her starting to take ginkgo. Her prothrombin time was found to be 16.9 seconds and her partial thromboplastin time was 35.5 seconds. She had been taking warfarin uneventfully for 5 years. The author of the report speculated that ginkgo may have contributed towards the haemorrhage.

Experimental evidence

In animal studies it was found that the AUC of warfarin was decreased by 23.4% when the ginkgo extract EGb 761 was given, and the prothrombin time was also reduced by EGb 761, which would suggest that ginkgo should reduce the effects of warfarin.

Mechanism

Uncertain. Isolated cases of bleeding have been reported with ginkgo alone (which have been the subject of a review). In pharmacological studies, ginkgo extract alone did not alter coagulation parameters or platelet aggregation. Moreover, the experimental study suggests that ginkgo might reduce the effects of warfarin. Ginkgo extracts also do not appear to affect the metabolism of a number of substrates of the cytochrome P450 isoenzyme CYP2C9, suggesting that a pharmacokinetic interaction with warfarin, which is metabolised by this route, is unlikely. Consider also Ginkgo + NSAIDs, and Ginkgo + Tolbutamide.

Importance and management

There is good evidence from pharmacological studies in patients and healthy subjects that ginkgo extract would not be expected to interact with warfarin. However, there is one case report of over-anticoagulation, and a few reports of bleeding with ginkgo alone. This is insufficient evidence to justify advising patients taking warfarin to avoid ginkgo, but they should be warned to monitor for early signs of bruising or bleeding and seek informed professional advice if any bleeding problems arise.

Consider also Ginkgo + Antiplatelet drugs, and Ginkgo + NSAIDs for other reports of bleeding events.