by Kerry Bone, BSc (Hons), Dip. Phyto, FNIMH, FNHAA, MCPP

Ginkgo biloba, as the 50:1 standardized extract (EGb), has been used as an herbal treatment for "cerebral insufficiency" and intermittent claudication for almost 40 years.¹

Journals now abound with articles attributing antiplatelet or even anticoagulant properties to ginkgo, warning against its concurrent use with aspirin or warfarin, and advising that it should be discontinued several weeks prior to surgery. For a typical example, see the article published in The Journal of The Royal Society for the Promotion of Health.² Cases linking EGb to spontaneous bleeding^3-8 and adverse interactions with warfarin⁹ and aspirin¹⁰ have been reported.

Two recently published cases associating ginkgo use with bleeding episodes are typical of the quality of the information. The first described a case of persistent postoperative bleeding following total hip arthroplasty.¹¹ The authors wrote: "Ginkgo biloba is an anticoagulant that inhibits platelet-activating factor and is contraindicated with aspirin...the Ginkgo was stopped, and the bleeding stopped six weeks later." The six-week time lag is hardly suggestive of a causative connection. The other case report concerned a 78-year-old man taking ginkgo who suffered a subdural hematoma following a fall.¹² Although the authors linked the ginkgo to the bleeding episode, the fall alone could have readily explained the presenting pathology.

The use of ginkgo is most widespread in Germany, where medical doctors commonly prescribe it. Until recently, the German authorities were largely silent on the issue of increased bleeding tendency, suggesting they were not concerned.

However, in 2002, an "Important Notice" was released from the Pharmaceutical Commission of German Pharmacists,¹³ which was in turn based on the publication of a summary of reports for ginkgo from the German adverse reactions database. By 2002, there were 185 reports of adverse reactions to ginkgo in Germany,¹⁴ of which 20 reports were supposedly connected to coagulation disorders. The commission warned that patients using ginkgo extracts are in danger of suffering spontaneous bleeding or complications during surgery, and that there is an increased danger of bleeding with concomitant use of anticoagulant drugs.

But the case against ginkgo is far from proven. The herb is one of the most popular in the Western world (for example, more than 5 million units of ginkgo products were sold in Germany alone in 1998)¹⁵ and because of its indications, ginkgo is largely taken by older people. So, the risk of spontaneous bleeding and the use of warfarin and aspirin are relatively high in the population typically taking ginkgo. The possibility therefore exists that haemorrhagic episodes are inappropriately attributed to ginkgo, when it is not the causative agent at all. In other words, a combination of ginkgo's reputation, its popularity and the demographics of its use lead to a self-fulfilling prophecy - that the herb is a risk for bleeding tendency.

There are in fact findings from several clinical studies challenging the assumption that ginkgo significantly alters bleeding parameters or interacts with antiplatelet or anticoagulant drugs. While a few early studies showed mild and probably insignificant effects, later studies failed to find any activity at all.

In studies with healthy volunteers, acute oral administration of high doses of standardized ginkgo extract (15 mL, probably corresponding to 600 mg dry extract) and a ginkgolide mixture (80 mg and 120 mg) inhibited PAF-induced platelet aggregation.^16-17

The effect with the ginkgo extract was only transient and there were no concomitant changes in coagulation, skin bleeding time, haematological and biochemical laboratory tests, blood pressure or pulse.¹⁶ Longer-term oral administration of the standardized extract at normal doses (120 mg/day for three months) resulted in inhibition of collagen-induced platelet aggregation, but failed to inhibit three other inducers, including PAF (1 _mol/L), ex vivo.¹⁸

Oral administration of standardised extract (112.5 mg) to healthy volunteers has been shown to reduce erythrocyte aggregation, but had no effect on plasma viscosity, platelet aggregation or blood pressure.²⁰ Another study reported a significant decrease in both diastolic and systolic blood pressure in healthy volunteers ingesting standardised extract (120 mg/day at bedtime) for three months, but bleeding times and fibrinogen levels showed no change.²¹

Fifty healthy male volunteers received either 240 mg/day of ginkgo extract or placebo for seven days in a randomized, crossover trial.²² Among the 29 coagulation and bleeding parameters assessed, none showed any evidence of being affected by ginkgo. The authors proposed that their study did not provide any evidence to substantiate a causal relationship between ginkgo and hemorrhagic complications.

Concomitant treatment with standardised ginkgo extract (100 mg/day) for four weeks in patients who were stabilised on long-term warfarin therapy had no significant influence on their response to warfarin in a randomised, double-blind, placebo-crossover trial (average age of patients was 64.5 years). The stability of international normalized ratio (INR) values was confirmed and major bleedings or thromboembolic events were not observed.²³ Administration of standardised ginkgo extract (240 mg/day) for seven days, alone or concomitantly with aspirin (500 mg/day), had no influence on bleeding parameters in a controlled trial involving 50 patients.²⁴

Based on the above, objective studies suggest that safety concerns regarding ginkgo and increased bleeding tendency are greatly exaggerated. Most case reports are inconclusive and of poor quality. The association of ginkgo with a few isolated events does not imply causality, and given its widespread use, the scarcity of such reports is testimony to its safety. No matter how often these concerns are recycled in biased or uncritical reviews, the objective reality is that the case is not proven. As a relatively recent review of ginkgo-drug interactions concluded:²⁵ "While caution and close monitoring of patients comedicating with Ginkgo (or other herbal product or drug) is recommended, the reporting of G. biloba-drug interactions appears exaggerated based upon the available evidence."

Much is made in the modern medical literature of evidence-based medicine (EBM). With EBM, controlled clinical trials represent a much higher level of evidence than isolated case reports. Hence, from an evidence-based perspective, it must be concluded that any link between the use of ginkgo and an increased bleeding tendency has not been substantiated.

Acknowledgment

The contribution of Michelle Morgan in the preparation of this article is gratefully acknowledged.