Ginkgo biloba is an extract from the dried leaves of Ginkgo biloba (maidenhair tree). In Germany, it is one of the most frequently prescribed supplements for cognitive disorders.
The leaf contains amino acids, flavonoids and terpenoids (including bilobalide and ginkgolides A, B, C, J and M).
The pharmacological properties of ginkgo biloba have been reviewed.1,2 Ginkgo biloba extract has the following properties. It:
- antagonises platelet activating factor (PAF), reducing platelet aggregation and decreasing the production of oxygen free radicals;3,4
2. increases blood flow, produces arterial vasodilatation and reduces blood viscosity;5 has free radical scavenging properties;6,7 and
3. may influence neurotransmitter metabolism.8
These effects are probably due to stimulation of prostaglandin biosynthesis or by direct vasoregulatory effects on catecholamines.6,9 In addition, ginkgo biloba acts as an antioxidant.10
Ginkgo biloba has been studied for the treatment of cerebrovascular disease and peripheral vascular insufficiency.
Memory and cognitive function
The main interest in ginkgo has focused on its use in patients with poor memory and poor cognitive function due to cerebral insufficiency, and it is licensed for this indication in Germany. A review of over 40 European clinical trials evaluated ginkgo’s efficacy in the treatment of cerebral and peripheral insufficiency.2,11 All 40 trials showed positive effects, and the authors concluded that there may have been publication bias. Of the 40 trials, eight were judged to be of good quality. The majority of studies evaluated 12 symptoms: difficulty in concentration; difficulty in memory; absent-mindedness; confusion; lack of energy; tiredness; decreased physical performance; depression; anxiety; dizziness; tinnitus and headaches. Seven of the eight trials showed statistically and clinically significant positive effects of ginkgo compared with placebo. No serious adverse effects were reported.
A meta-analysis of 11 placebo-controlled, randomised, double-blind studies (which included six of the studies) showed that ginkgo was significantly better than placebo for all symptoms associated with cerebrovascular insufficiency of old age. Of the 11 studies, one study was inconclusive, but all the rest showed positive effects.12
In a double-blind, placebo-controlled study, 31 patients over the age of 50 years were randomised to receive gingko biloba 40 mg or placebo three times a day. Using a range of psychometric tests, ginkgo was shown to produce a significant improvement in cognitive function at both 12 and 24 weeks.13 More recent double-blind, placebo-controlled trials have confirmed the benefits of ginkgo on memory14 and cognitive function.15
However, in a 6-week RCT, involving 98 men and 112 women over the age of 60 with no cognitive impairment, gingko biloba 40 mg three times a day did not facilitate performance on standard neuropsychological tests of learning, memory, attention and concentration, or naming and verbal fluency. The ginkgo group also did not differ from the control group in terms of self-reported memory function or global rating by spouses, friends and relatives. The authors concluded that ginkgo provides no measurable benefit in memory or related cognitive function to adults with healthy cognitive function.16
Effects of gingko biloba in young adults have been less well characterised. A double-blind, placebo-controlled trial in 19 men and 23 women (mean age 23.6 years) investigated the effect of ginkgo biloba (mean dose 184.5 mg daily) on various alertness, performance, affective state and chemosensory tests after meals over a 13-week period. Ginkgo biloba was found to be ineffective at alleviating the symptoms of post-lunch dip or at enhancing smell and taste function.17
A double-blind RCT in 52 students found that an acute dose of ginkgo significantly improved performance in tests of attention and memory. However, there were no effects on working memory, planning, mental flexibility or mood. Moreover, after 6 weeks of treatment, there were no significant effects of ginkgo on mood or any of the cognitive tests, suggesting that tolerance developed to the effects, at least in this young healthy population.18
Ginkgo biloba has also been investigated for effects on cognition and mood in post-menopausal women. In one small controlled trial, ginkgo 120 mg daily for 7 days was associated with significantly better non-verbal memory, sustained attention and frontal lobe function than placebo. However, the two groups did not differ in tests of planning, immediate or delayed paragraph recall, delayed recall of pictures, menopausal symptoms, sleepiness, physio-logical symptoms or aggressive behaviour.19 In a further trial, post-menopausal women (aged 51–67 years) were randomly allocated to receive ginkgo 120 mg daily for 6 weeks. The only significant effects of ginkgo were limited to the test of mental flexibility, and also to those with poorer performance, who were mainly in the late stages of menopause (mean age 61 years).20
Peripheral vascular disease
In the review of 40 trials mentioned above,11 15 controlled trials evaluated the role of ginkgo in intermittent claudication, and of these, two were judged to be of reasonable quality. One showed significant increase in walking distance tolerated before pain with ginkgo,21 and the other showed a greater reduction in pain at rest.22
In a multicentre, randomised, double-blind, placebo-controlled study involving 74 patients with peripheral arterial occlusive disease, pain-free walking distance improved in patients given either 120 or 240 mg ginkgo biloba daily, with a greater improvement in the group given the higher dose.23
In another multicentre, double-blind, placebo-controlled trial, 111 patients with peripheral occlusive arterial disease were randomised to receive 120 mg ginkgo biloba extract or placebo for 24 weeks. Pain-free walking and maximum walking distance were significantly greater in the ginkgo group and subjective assessment by the patients showed an amelioration of complaints in both groups.24
A meta-analysis of eight RCTs with 415 participants concluded that ginkgo biloba extract is superior to placebo in the symptomatic treatment of intermittent claudication. However, the size of the overall treatment effect is modest and of uncertain clinical relevance.25 A more recent double-blind trial in patients with Reynaud’s disease found that ginkgo biloba reduced the number of attacks of digital ischaemia by 56% whereas placebo reduced the number by 27%.26
In a double-blind, placebo-controlled trial, 216 patients with Alzheimer’s disease were randomised to receive either 240 mg ginkgo biloba EGb 761 extract or placebo for 24 weeks. In the 156 patients who completed the study, the frequency of responders in the two groups differed significantly in favour of EGb 761. Analysis of the results on an intention-to-treat basis showed similar results and the authors concluded that EGb 761 was beneficial in dementia of the Alzheimer type and in multi-infarct dementia.27 A 52-week, randomised, double-blind, placebo-controlled, parallel-design, multicentre study in 309 patients found that EGb 761 120 mg daily improved measures of cognitive function, daily living, and social performance and psychopathology. The authors concluded that ginkgo was safe and capable of maintaining, or in some cases improving, cognitive and social function in patients with dementia.28 Of the 309 patients, 244 completed the study up to 26 weeks, but analysis on an intention-to-treat basis still showed significant benefits with ginkgo biloba.29
A review of 50 articles, of which four randomised, placebo-controlled, double-blind trials met the inclusion criteria, concluded that there is a small but significant effect of 3– 6 months of treatment with 120–240 mg of ginkgo biloba extract on objective measures of cognitive function in Alzheimer’s disease.30
However, in another study of 214 elderly patients with dementia or memory impairment, who were split into three groups and given one of two different doses of ginkgo biloba extract EGb 761 or a placebo, no differences were detected in memory function after 24 weeks.31 The authors suggested that these results came about because of the effort made to find a good placebo (ginkgo has a pronounced taste and smell). However, others have questioned the validity of the study, suggesting that a positive effect would have been unlikely in such a heterogeneous population where all types of memory loss were included.32
Ginkgo biloba has not been directly compared to conventional medicines for dementia, but improvement seems to be similar to that found with prescription drugs (e.g. donepezil, tacrine and possibly other cholinesterase inhibitors).33,34
More recent trials have shown inconsistent results. A 24-week RCT in 214 patients with dementia or age-associated memory impairment did not find a significant effect of ginkgo (special extract EGb 761) treatment. There was no dose–effect relationship and no effect of prolonged ginkgo treatment.35 However, intention-to-treat analysis of another study concluded that ginkgo (EGb 761) improves cognitive function in a clinically relevant manner in patients suffering from dementia.36 A review comparing different doses of ginkgo biloba with cholinesterase inhibitors in the treatment of dementia found significant benefits on cognition with cholinesterase inhibitors, but only with ginkgo when all doses were pooled.37 An RCT in 513 patients with dementia of the Alzheimer’s type did not show efficacy of ginkgo. However, there was little cognitive and functional decline in the placebo-treated patients, which may have compromised the sensitivity of the trial to detect a treatment effect. This study was therefore inconclusive with respect to the efficacy of ginkgo biloba.38 A Cochrane review concluded that overall there is promising evidence of improvement in cognition and function associ-ated with ginkgo. However early trials, which showed beneficial results, used unsatisfactory methodology and more modern trials, with better methodology, show inconsistent results. There is need for a large trial using modern methodology with intention-to-treat analysis to provide robust estimates of the size and mechanism of any treatment effects.39
There are many reports in the literature that ginkgo biloba may be effective in tinnitus. However, recent trials suggest there is little evidence of benefit. An RCT in 66 adults together with six further RCTs were meta-analysed, and ginkgo was found not to benefit patients with tinnitus.40 A Cochrane review of 12 trials excluded 10 trials on methodological grounds. No trials of tinnitus in cerebral insufficiency reached a satisfactory standard for inclusion in the review and there was no evidence that ginkgo was effective for the primary complaint of tinnitus.41
Ginkgo biloba has been claimed to be of value in a number of other conditions, including asthma, sexual dysfunction, PMS and mountain sickness. However, there is only very limited evidence that ginkgo biloba has any benefit in these conditions. A review (which included one study) of the role of ginkgo in ARMD concluded that, although a beneficial effect was observed, only 20 people were enrolled in the trial and assessment was not masked, thus making the results equivocal.42 A Cochrane review of ginkgo biloba for acute ischaemic stroke concluded that the methodological quality of the trials to date had been too poor to support the routine use of ginkgo biloba to promote recovery after stroke.43 Further research is needed in all these areas.
Ginkgo biloba should not be used for the treatment of disease without medical supervision. It is contraindicated in hypertension. Ginkgo has been associated with increased bleeding tendency. However, a recent trial showed no evidence that EGb 761 inhibits blood coagulation, platelet aggregation and haemorrhagic complications.44 There is anecdotal evidence that ginkgo might be associated with seizure, so until more is known, ginkgo should be avoided in epilepsy or in patients at risk of seizure. There is also preliminary evidence that ginkgo increases insulin clearance,45 and this should be borne in mind in monitoring blood glucose in diabetes.
Pregnancy and breast-feeding
Contraindicated in pregnancy, breast-feeding and in children.
There are few reports of serious toxicity. Headache, nausea, vomiting, heartburn and diarrhoea have been reported occasionally. There have been rare reports of severe allergic reactions, including skin reactions (e.g. itching, erythema and blisters) and convulsions.
Anticoagulants, aspirin, anti-platelet drugs: use ginkgo biloba with caution. However, a recent study showed no effect of ginkgo on the pharmacodynamics and pharmacokinetics of warfarin in healthy patients.46
There is preliminary evidence that ginkgo can influence cytochrome P450 and other drug-metabolising enzymes.47 There are no reports of interactions, but ginkgo should be used with caution in any patients taking other medication.
Ginkgo biloba is available in the form of tablets, capsules and tincture. A review of 30 US ginkgo biloba products found that nearly one-quarter did have the expected chemical marker compounds for ginkgo biloba extract (e.g. flavone glycosides, terpene lactones).48
Most clinical trials have used a 50:1 concentrated leaf extract (EGb 761) standardised to 24% flavone glycosides and 6% terpene glycones. (A standardised 40 mg tablet should therefore contain 9.6 mg flavone glycosides and 2.4 mg terpene glycones.) Studies have used 120–240 mg daily. Dietary supplements provide 40–80 mg in a dose.
Several studies have shown that gingko biloba may slow the progression of dementia, particularly in Alzheimer’s disease. There is also some evidence that gingko improves memory and concentration in the elderly and increases pain-free walking and maximum walking distance in those with peripheral vascular disease. However, ginkgo should not be taken in any of these conditions without medical advice. There is no sound evidence that ginkgo is effective in other conditions.
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