Ginkgo biloba is a complex herb that contains many different active constituents and works by means of multiple mechanisms. In practice, its therapeutic effect is a result of interactions between constituents and mechanisms, giving it applications in many varied conditions. To date, most of the research conducted in Europe has used a standardised preparation known as EGb 761, available commercially as Rokan, Tanakan or Tebonin.
DEMENTIA, MEMORY IMPAIRMENT
Ginkgo biloba has been used and studied as a cognitive activator in a variety of populations, such as cognitively intact people, those with cerebral insufficiency, age-related memory impairment, Alzheimer’s dementia or multi-infarct dementia.
A 2002 Cochrane review of the scientific literature concluded that Ginkgo biloba produces benefits superior to placebo within 12 weeks’ treatment in people with acquired cognitive impairment, including dementia, of any degree of severity. Cognition, activities of daily living and measures of mood and emotional function show significant benefit for ginkgo compared with placebo.
Some clinical studies have also found that EGb 761 improves the capacity of geriatric patients to cope with the stressful demands of daily life.
Clinical note — What is cerebral insufficiency?
Cerebral insufficiency is a syndrome characterised by a collection of symptoms, although it is not associated with any clear pathological changes. The 12 symptoms associated with this condition are: difficulties of memory and concentration; being absent-minded; confusion; lacking energy; tiredness; decreased physical performance; depressive mood; anxiety; dizziness; tinnitus; and headaches. Some of these symptoms are also described as early symptoms of dementia and appear to be associated with decreased cerebral blood flow, although frequently no explanation is found.
Use in healthy subjects
A number of double-blind studies have investigated the effects of Ginkgo biloba (150-600 mg/day) in healthy subjects; however, it remains unclear whether benefits can be expected in this population.
A 6-week, double-blind placebo-controlled trial using a dose of 180 mg/day EGb 761 extract in healthy elderly subjects found that active treatment produced significantly better improvements on a task assessing speed of processing abilities compared with placebo. Subjectively, more people rated their ability to remember as improved by the end of treatment with ginkgo compared with placebo, but no significant differences were found between the groups on any of the four objective memory measures. Another randomised, double-blind placebo-controlled study involving 31 subjects (aged 30-59 years) compared the effects of four different doses of ginkgo extract with placebo over 2 days. Once again, treatment improved various aspects of cognition with the strongest effects seen on memory. A dose of 120 mg ginkgo extract daily produced the best effects, and cognitive-enhancing effects were most apparent in the group aged 50-59 years.
Two more clinical studies to investigate ginkgo in cognitively intact older adults have produced conflicting results. Solomon et al used a dose of 120 mg/day over 6 weeks under double-blind conditions and found no significant differences between treatment and control groups on any outcome measure that included standard neuropsychological tests for memory and concentration. There have been several points of controversy regarding this particular trial, chiefly in regard to the non-identical placebo that was used (a soft gelatin capsule for placebo whereas the ginkgo product was a film-coated tablet). Mix and Crews used a higher dose of 180 mg/day over 6 weeks under the same test conditions and found that people receiving EGb 761 exhibited significantly more improvement on several neuropsychological tests, indicating improved aspects of memory. Additionally, the results of self-rated surveys found that memory improvements were of sufficient magnitude as to be detected by participants in the ginkgo treatment group.
Comparisons with anticholinesterase drugs
The type of CNS effects produced by EGb 761 in elderly dementia patients is similar to those induced in tacrine responders and those seen after the administration of other ‘cognitive activators’, according to a small randomised study involving 18 elderly people diagnosed with mild to moderate dementia (possible or probable Alzheimer’s disease). The results also demonstrated that 240 mg EGb produced typical cognitive activator ECG profiles (responders) in more subjects (8 of 18) than 40 mg tacrine (3 of 18 subjects). A later review concluded that ginkgo extract and second-generation cholinesterase inhibitors (donepezil, rivastigmine, metrifonate) should be considered equally effective in the treatment of mild to moderate Alzheimer’s dementia.
Commission E approves the use of standardised ginkgo extract in dementia syndromes, including vascular, primary degenerative and mixed types.
The many mechanisms attributed to ginkgo make it an ideal candidate for the long-term prevention of many age-related diseases such as dementia. Currently, a large study involving more than 3000 volunteers is underway in the United States. The Ginkgo Evaluation of Memory (GEM) study will evaluate whether long-term ginkgo use will reduce the incidence of all-cause dementia and Alzheimer’s dementia. Secondary outcomes of the trial include measuring effects on the rate of cognitive and functional decline, incidence of cardiovascular and cerebrovascular events, and mortality.
Acute ischaemic stroke
Ginkgo biloba extract is widely used in the treatment of acute ischaemic stroke in China. A Cochrane systematic review identified 14 trials of which 10 (792 patients) were included. In those 10 trials, follow-up was performed at 14-35 days after stroke and in all studies neurological outcome was assessed, but none of them reported on disability (activities of daily living function) or QOL and only three trials reported adverse events. Nine of the trials were considered to be of inferior quality. Overall results from the 10 studies found that Ginkgo biloba extract was associated with a significant increase in the number of improved patients. Of note, one placebo-controlled trial, assessed to be of good quality, failed to show an improvement of neurological deficit at the end of treatment. In view of the short-comings of many trials and limited evidence, high-quality and large-scale randomised controlled trials are still required to determine its efficacy.
Although studies investigating the effects of Ginkgo biloba in cerebral insufficiency, a syndrome that is often characterised by depression, have shown positive results, no clinical studies are available that have investigated its use in clinical depression. One randomised, double-blind placebo-controlled study has investigated its effects in seasonal affective disorder (SAD). Ginkgo biloba extract PN246, in tablet form (Bio-Biloba), was tested in 27 patients with SAD over 10 weeks or until they developed symptoms, starting in a symptom-free phase about 1 month before symptoms were expected. In this trial, Ginkgo biloba failed to prevent the development of SAD.
More recently, Cieza et al (2003) tested EGb 761 (240 mg/day) on the subjective emotional well-being of healthy older subjects (50-65 years) in a randomised, double-blind study. Ginkgo treatment produced a statistically significant difference fortheVAS mental health and for QOL, as well as for the Subjective Intensity Score Mood in week 2 compared with placebo. At the end of the study, statistically significant improvement in the EGb 761 group was observed for the variables: depression, fatigue and anger.
GENERALISED ANXIETY DISORDER
EGb 761 has demonstrated stress-alleviating and anxiolytic-like activity in preclinical studies, and most recently in a randomised study of 107 patients with GAD (n = 82) or adjustment disorder with anxious mood (n = 25). Ginkgo biloba was tested in two different doses (480 mg and 240 mg/day) against placebo over 4 weeks and found to be significantly superior with a dose-response trend being identified. Beneficial effects were observed after 4 days of treatment.
PERIPHERAL VASCULAR DISEASES
Ginkgo has been used in the treatment of intermittent claudication, Raynaud’s syndrome and chilblains.
In 2000, a meta-analysis of eight clinical trials found a significant difference in the increase in pain-free walking distance in favour of Ginkgo biloba over placebo in intermittent claudication. An earlier randomised study measuring transcutaneous partial pressure of oxygen during exercise showed that a dose of 320 mg/day EGb 761 taken for 4 weeks significantly decreased the amount of ischaemic area by 38% compared with no change with placebo.
A more recent 2004 meta-analysis confirmed that ginkgo is more effective than placebo in intermittent claudication. Nine double-blind studies of EGb 761 for intermittent claudication were assessed in a total of 619 patients. A sensitivity analysis of a homogeneous sample in terms of design, treatment duration, inclusion and exclusion criteria and methods of measurement confirms these findings. Most studies have used a dose of 120 mg/day taken in divided doses, although one trial found 240 mg/day gave better results. It should be recommended as long-term therapy and as an adjunct to exercise for the best results.
Commission E approved the use of standardised ginkgo extract for intermittent claudication.
Clinical note — Peripheral arterial disease
Peripheral arterial disease (PAD) is the chronic obstruction of the arteries supplying the lower extremities. The most frequent symptom is intermittent claudication, which results from poor oxygenation of the muscles of the lower extremities and is experienced typically as an aching pain, cramping, or numbness in the calf, buttock, hip, thigh, or arch of the foot. Symptoms are induced by walking or exercise and are relieved by rest. Presently, medical treatment revolves around lifestyle changes, such as increased exercise, and surgery as a final option.
A standardised Ginkgo biloba extract (Seredrin) taken over a 10-week period significantly reduced the number of attacks per week (from 13.2 to 5.8) compared with placebo, according to a randomised study.
VERTIGO, TINNITUS AND SUDDEN DEAFNESS
Ginkgo is used to treat these and other symptoms of vestibule-cochlear disorders.
In 1999, a systematic review of five RCTs testing standardised Ginkgo biloba extracts in people whose primary complaint was tinnitus concluded that treatment with Ginkgo biloba may result in significant improvements in tinnitus. Three years later, a review of eight controlled trials in tinnitus confirmed these findings, stating that ginkgo is significantly superior to placebo or reference drugs when used for periods of 1 -3 months.
However, results of two double-blind studies conducted more recently have shifted the evidence against the use of Ginkgo biloba in tinnitus. The first was a large, double-blind, placebo-controlled study involving 1121 people aged between 18 and 70 years with tinnitus and 978 matched controls, which found that 12 weeks of treatment with ginkgo extract, LI 1370 (Lichtwer Pharma, Berlin, Germany), 50 mg, three times daily resulted in no significant differences when subjects assessed their tinnitus in terms of loudness and how troublesome it was. A more recent double-blind, placebo-controlled, randomised study of 66 subjects with tinnitus failed to show benefits with active treatment using a dose of 120 mg extract daily over 12 weeks. The primary outcome measures used were the Tinnitus Handicap Inventory, The Glasgow Health Status Inventory and the average hearing threshold at 0.5, 1, 2 and 4 kHz. In 2004, Rejai et al conducted a meta-analysis of clinical trials and found that 21.6% of patients with tinnitus reported benefit from Ginkgo biloba versus 18.4% of patients who reported benefit from a placebo.
A 2004 Cochrane systematic review came to a similar conclusion, reporting that the limited evidence currently available does not support the use of ginkgo in tinnitus; however, the authors also pointed out that if a greater level of understanding and diagnostic accuracy could be reached about the different aetiologies of tinnitus, this may naturally highlight subgroups of patients in whom further controlled trials of Ginkgo biloba are worth considering.
Salicylate-induced tinnitus One in vivo study investigating the effects of ginkgo in salicylate-induced tinnitus found a statistically significant decrease in the behavioural manifestation of tinnitus for ginkgo in doses of 25, 50 and 100 mg/kg/day.
Sudden deafness Ginkgo extract was as effective as pentoxifylline in the treatment of sudden deafness, according to one randomised double-blind study. Both treatments equally reduced associated symptoms of tinnitus and produced the same effects on the return to normal of speech discrimination. Subjective assessment suggested that Ginkgo biloba extract was more beneficial than pentoxifylline. EGb 761 (240 mg/day) has also been shown to accelerate and secure recovery of acute idiopathic sudden sensorineural hearing loss, observable within 1 week of treatment under randomised double-blind test conditions.
Commission E approves the use of standardised ginkgo extract in these conditions when of vascular origin.
MACULAR DEGENERATION, GLAUCOMA AND RETINOPATHY
In regard to these opthalmological conditions, ginkgo has numerous properties that should theoretically make it a useful treatment, such as increasing ocular blood flow, antioxidant and platelet-activating factor inhibitor activity, NO inhibition and neuroprotective abilities.
Although some positive evidence exists, a 2000 Cochrane review has suggested overall there is insufficient evidence currently available to conclude that Ginkgo biloba treatment is effective in macular degeneration, with further testing required.
In regard to glaucoma, the little research conducted so far appears promising.
Researchers using colour Doppler imaging have observed significantly increased end-diastolic velocity in the ophthalmic artery after treatment with EGb (120 mg/day) in a placebo-controlled, randomised crossover study. A randomised, double-blind crossover study found that EGb 761 (120 mg/day) taken for 4 weeks produces positive effects in normal tension glaucoma. Furthermore, ginkgo treatment did not significantly alter intraocular pressure, blood pressure or heart rate and was well tolerated.
In vivo tests using electroretinography have identified protective effects against the development of chloroquine-induced retinopathy using Ginkgo biloba. This has been observed in both acute and chronic chloroquine toxicity of the retina.
PREVENTION OF ALTITUDE SICKNESS
Four randomised studies have investigated Ginkgo biloba as prophylactic treatment against altitude sickness, producing mixed results. One study involving 44 subjects found that a dose of 150 mg/day taken for 5 days as prophylactic treatment resulted in no subject developing the cerebral symptoms of acute mountain sickness versus 41% of subjects in the placebo group. Whereas only three subjects (13.5%) in the EGb 751 group developed respiratory symptoms of acute mountain sickness, 18 (81.8%) in the placebo group developed these symptoms. Besides effectively preventing mountain sickness for moderate altitude (5400 m), treatment also decreased vasomotor disorders of the extremities. A second study showed that Ginkgo biloba 180 mg/day started 24 hours before rapid ascent from sea level to 4205 m significantly reduced altitude sickness under double-blind test conditions. The two more recent studies compared ginkgo to placebo and acetazolamide and found no significant effects for ginkgo. The largest study was conducted by Gertsch et al and involved 487 healthy Western hikers. It compared the effects of ginkgo, acetazolamide (250 mg), combined acetazolamide and ginkgo, and placebo. Participants took at least 3-4 doses before ascent above 4000 m in the Nepal Himalayas. The incidence of acute mountain sickness was 34% for placebo, 12% for acetazolamide, 35% for ginkgo and 14% for combined ginkgo and acetazolamide. Chow et al conducted a smaller study of 57 healthy unacclimatised subjects using a randomised, placebo-controlled design. Subjects were taken to an elevation of 3800 m within 24 hours, with acetazolamide producing significantly better effects than ginkgo or placebo using the Lake Louise Acute Mountain Sickness Scoring System. Subjects receiving ginkgo were as likely as placebo to experience acute mountain sickness whereas acetazolamide was protective.
A randomised double-blind study evaluating the effects of EGb 751 in treating congestive symptoms of PMS in a group of 155 women found that treatment over two menstrual cycles (from day 15 until day 5 of the next cycle) was successful.
Treatment was particularly effective in reducing breast symptoms, although neuropsychological symptoms were also alleviated.
A dose of 120 mg/day ginkgo extract significantly stopped active progression of depigmentation in slow-spreading vitiligo and induced repigmentation in some treated patients under double-blind, placebo-controlled study conditions. Although the mechanism of action responsible is unknown, antioxidant activity is thought to be important.
Ginkgo significantly reduced airway hyperreactivity, improved clinical symptoms and pulmonary function in asthmatic patients in one placebo-controlled study. Platelet-activating factor inhibitor, antioxidant and anti-inflammatory activities are likely to be involved.
Due to its vasodilatory effects, ginkgo has been used in the management of sexual dysfunction in cases where compromised circulation is suspected. One open study has been conducted with subjects experiencing sexual dysfunction associated with antidepressant use.
Ginkgo extract (average dose 209 mg/day) was found to be 84% effective in treating antidepressant-induced sexual dysfunction, predominantly caused by SSRI, in a study of 63 subjects. A relative success rate of 91 % was observed for women compared with 76% for men and a positive effect was reported on all four phases of the sexual response cycle: desire, excitement (erection and lubrication), orgasm and resolution. Although this was an open trial, the results are encouraging when one considers the placebo effect is about 25% from past randomised trials of FDA-approved medications for erectile dysfunction.
More recently, a small triple-blind (investigator, patient, statistician), randomised, placebo-controlled, trial of Ginkgo biloba (240 mg/daily for 12 weeks) was undertaken with 24 subjects experiencing sexual impairment caused by antidepressant drugs. The authors report some spectacular individual responses in both groups, but no statistically significant differences, and no differences in side-effects.
There is great interest in the application of safe substances, such as Ginkgo biloba, in neurodegenerative diseases such as Parkinson’s disease because of their neuroprotectiveand mitochondrial protective effects. Currently, investigation with ginkgo is limited to animal studies of experimentally induced Parkinson’s disease, which have shown it to afford some protection against neuronal loss.