Ginkgo flavone glycoside

Other Names

flavone glycosidesflavonoid glycosidesflavonoid heteroglycosidesflavonoid heterosidesflavonol glycosidesginkgo biflavonoidsginkgo biloba flavone glycosidesGinkgo biloba leaf flavonoidsginkgo flavoglycosidesginkgo flavone glycosidesginkgo flavoneglycosidesginkgo flavonesginkgo flavonglycosidesginkgo flavonoid glycosidesginkgo flavonoides glycosidesginkgo flavonoidsginkgo flavonol glycosidesginkgo flavonyl glycosidesginkgo heterosidesginkgoflavoglycosidesginkgoflavone glycosidesginkgoflavoneglycosidesginkgoflavonesginkgoflavonglycosidesginkgoflavonoid glycosides

Synopsis

Ginkgo Flavone Glycosides: A Comprehensive Encyclopedic Reference

1. Identity: Botanical Origin, Chemical Names, and Nomenclature

Botanical source. Ginkgo flavone glycosides (GFGs) are a class of polyphenolic compounds derived exclusively from Ginkgo biloba L. (family Ginkgoaceae), the maidenhair tree. A true survivor of history, Ginkgo biloba appeared over 270 million years ago and is considered the world's oldest tree species. Although Ginkgo biloba and other species of the genus were once widespread throughout the world, its habitat had shrunk by two million years ago; for centuries it was thought to be extinct in the wild, but is now a common tree cultivated throughout eastern China, Korea, and Japan. It is traditionally as well as economically important, now cultivated in China, Japan, Korea, France, Germany and in some parts of India, especially in Uttarakhand state, for its aesthetic and the medicinal value.

Chemical identity. The term "ginkgo flavone glycosides" refers collectively to the flavonoid fraction of standardized Ginkgo biloba leaf extract. Ginkgo biloba leaves contain a number of substances from this group, including flavonol glycosides, biflavones, proanthocyanidins, and isoflavonoids; however, the majority are the multiform glycosides of quercetin, kaempferol, and isorhamnetin. The flavonoids frequently occur as glycoside derivatives; quercetin, kaempferol, and isorhamnetin are the principal flavonoids in Ginkgo biloba and are structurally related. Isorhamnetin, quercetin, and kaempferol are the major sources of flavonol glycosides and are linked via rhamnose and glucose in various forms; the mono-, di-, and tri-glycanic moieties are at the C-3 position.

Aglycone diversity. One hundred ten flavonoids belonging to seven classes have been identified in ginkgo extracts; the first class consists of 52 glycosides of flavonols and seven flavonols. Known aglycones of flavonol glycosides include quercetin, kaempferol, and isorhamnetin; in addition, from the group of aglycons, there are also syringetin, myricetin, laricitrin, myricetin 3′,4′-dimethyl ether, and patuletin. To date, over 70 flavonoids have been isolated from ginkgo leaves; most can be categorized into four groups: flavones, flavonols, biflavonoids, and catechins. Ginkgo flavones mainly include apigenin, luteolin, and chrysin; ginkgo flavonols contain quercetin, kaempferol, and isorhamnetin. Biflavonoids are a class of compounds formed by the polymerization of two flavonoid cores through C-C bonds; a total of 13 biflavonoids, including bilobetin, amentoflavone, sequoiaflavone, sciadopitysin, and podocarpusflavone A, have been identified in G. biloba.

Relationship to the whole extract. Ginkgo extract contains over 60 bioactive ingredients, but the most important role is played by flavonoids and terpenoids; they usually constitute about 24% and 6% of the extract, respectively. The other major chemical class — the terpene trilactones (ginkgolides A, B, C, J, M and bilobalide) — is chemically distinct from the flavone glycosides but co-occurs with them in standardized preparations. Important constituents present in the medicinally used leaves are the terpene trilactones, i.e., ginkgolides A, B, C, J, and bilobalide, many flavonol glycosides, biflavones, proanthocyanidins, alkylphenols, simple phenolic acids, 6-hydroxykynurenic acid, 4-O-methylpyridoxine, and polyprenols.

2. Natural Source, Commercial Forms, and Preparations

Plant part used. The Ginkgo biloba extract marketed in Europe is a well-defined product prepared from the green leaves, containing at least 26 identified components, and standardized to contain 24% flavonoid glycosides (ginkgo flavone glycosides) and 6% terpenoids (ginkgolides and bilobalide). For herbal supplements, usually a G. biloba leaf extract is used, although the seeds can also be used in dietary supplements; however, in the scientific literature, only effects of the standardized leaf extract are supported.

The reference extract: EGb 761®. EGb 761 is a standardized extract of dried leaves of Ginkgo biloba containing 24% ginkgo-flavonol glycosides and 6% terpene lactones such as ginkgolides A, B, C, J, and bilobalide. In the early 1970s, Dr. Willmar Schwabe Pharmaceuticals (Karlsruhe, Germany) effectively developed a method for the extraction and standardization of Ginkgo biloba extract preparation and produced highly concentrated and stable extracts from Ginkgo biloba leaves. EGb 761® is a dry extract from Ginkgo biloba leaves (35–67:1), extraction solvent: acetone 60% (w/w); the extract is adjusted to 22.0–27.0% ginkgo flavonoids calculated as ginkgo flavone glycosides and 5.0–7.0% terpene lactones consisting of 2.8–3.4% ginkgolides A, B, C, and 2.6–3.2% bilobalide, and contains less than 5 ppm ginkgolic acids.

Extraction methodology and pharmacopeial specifications. Leaf extracts can be divided into two types: whole-leaf and standardized; whole-leaf extracts are typically obtained using alcohol and contain alcohol-soluble components, whereas standardized extracts are prepared via a multistep process. Some compounds (terpene trione and flavonoids) are concentrated, whereas others (biflavones and ginkgolic acid) are removed; the standardized extracts include 6% terpene trione, 24% flavonoid glycosides, and less than 5 ppm ginkgolic acid. The European Pharmacopoeia requires that dried G. biloba leaf is to be extracted with 60% acetone (m/m) as primary extraction solvent and the final product is adjusted to 22.0%–27.0% ginkgo flavonoids calculated as ginkgo flavone glycosides and 5.4%–6.6% terpene lactones consisting of 2.8%–3.4% ginkgolides A, B, C, and 2.6%–3.2% bilobalide, and contains less than 5 ppm ginkgolic acids. The Chinese and US pharmacopoeias deviate in part from these specifications; the US specification for flavonol glycosides and ginkgolic acids are the same as the European, but the specification for terpene trilactones can be 5.4%–12.0%. The Chinese pharmacopoeia specifies only lower limits of at least 6% terpene trilactones and at least 24% flavonol glycosides with no upper limits.

Dosage forms. GBE can be incorporated into liquid or tablet preparations. The extract is commercially available in capsules, tablets, liquid tinctures, and as a component of injectable pharmaceutical preparations used in some countries. Shuxuening injection (SXNI), one of the pharmaceutical preparations of Ginkgo biloba extract, has significant effects on both ischemic stroke and heart diseases from bench to bedside. Phytopharmaceutical extracts from the leaves of Ginkgo biloba have been applied to treat cerebrovascular and peripheral vascular diseases in many countries, such as Germany, France, Japan, and Korea since the 1960s.

Analytical quantification. After acidic hydrolysis to the aglycones quercetin, kaempferol, and isorhamnetin and separation by HPLC, quantitation is straightforward and yields by recalculation an estimation of the original total flavonol glycoside content. EGb 761 is standardized to contain 24% ginkgo-flavone glycosides and 6% terpenoid lactones with major constituents including flavonol monoglycosides (e.g., quercetin-3-O-glucoside, quercetin-3-O-rhamnoside), flavonol diglycosides, flavonol triglycosides, coumaric esters of flavonol diglycosides, and flavonoidic compounds.

3. Traditional and Historical Use

China — early written records. Ginkgo biloba first appears in written Chinese records around 1000 CE and is referred to as a "nut tree"; it is likely that ginkgo nut-like seeds were used as a food source for thousands of years by the early inhabitants of what is now modern-day China, and the early written records indicate that ginkgo was also first cultivated around 1000 CE. Preparations of Ginkgo biloba leaves have been used as remedies in China for more than 5,000 years, i.e., since the earliest origin of Chinese herbal medicine.

Traditional Chinese medicine (TCM) applications. Ginkgo biloba, or Bai guo, is one of the most well-studied Chinese herbs; edible nut-like seeds were used for a long time in traditional Chinese medicine to manage symptoms associated with dysfunction of heart and lung; later, neuroprotective properties of Ginkgo biloba were discovered, and today the most common use of G. biloba extract is to sharpen memory and improve blood circulation. Ginkgo seeds are also a very important ingredient in traditional Chinese medicine for the treatment of respiratory, urinary, and mental health issues. Ginkgo kernels are also used in traditional Chinese medicine, notably to treat respiratory ailments such as coughs, bronchitis, and asthma. More broadly, in traditional Chinese medicine, G. biloba preparations have been used for centuries for the management of disorders such as anxiety, allergy, dementia, eye problems, peripheral artery disease, tinnitus, liver fibrosis, hepatocellular carcinoma, and cardiovascular health.

Traditional preparation methods. Ginkgo leaves were traditionally brewed into teas or incorporated into herbal remedies to treat various ailments, including respiratory issues, circulatory problems, and cognitive decline. During the Medieval period, ginkgo was variously referred to by different names, such as "silver apricot," "white fruit," "white eye," the "grandfather–grandchild tree," and "duck foot."

Japan and Korea. It was around this time (the Medieval period) that ginkgo was introduced to Japan and Korea. In Japan, G. biloba nuts have been eaten as a side dish since the Edo Period (1600–1867). In Japan and Korea, ginkgo has also held a prominent place in traditional medicine for centuries; Japanese monks cultivated ginkgo trees in temple gardens, where they were revered for their beauty and perceived spiritual significance.

Introduction to Europe. At the beginning of the 18th century, it came to Europe on trade routes from Japan, where it has been cultivated as an ornamental plant since then. The Western pharmaceutical use of standardized leaf extract began in earnest in the 1960s with the development of concentrated proprietary preparations.

4. Key Constituents and Active Compounds

Overview of the flavone glycoside fraction. Quercetin, kaempferol, and isorhamnetin are the principal flavonoids in Ginkgo biloba and are structurally related. Kaempferol is a metabolite of quercetin, and isorhamnetin is a metabolite of kaempferol. Identified ginkgo flavonol glycosides include quercetin, kaempferol, myricetin, apigenin, isorhamnetin, luteolin, and tamarixetin. The glycoside sugar attachments include rhamnose and glucose in mono-, di-, and triglycosidic configurations at the C-3 position.

Other co-occurring flavonoid subclasses. The catechins in G. biloba can be classified into four types: catechins, epicatechin, gallic acid catechins, and epigallic acid catechins, and their corresponding dimers. Notable minor flavonoid-related compounds include acylated flavonol glycosides (ginkgoghrelins) and biflavones (ginkgetin).

Terpene fraction for context. Ginkgolides and bilobalide are major constituents of the terpene trilactones; for years, researchers have prepared ginkgolides, which include ginkgolide A (GA), ginkgolide B (GB), ginkgolide C (GC), ginkgolide J (GJ), ginkgolide K (GK), ginkgolide L (GL), and ginkgolide M (GM), and investigated their effectiveness toward multiple diseases. Bilobalide is a sesquiterpene and an active constituent of G. biloba extract.

Additional minor constituents. Other constituents such as glucose, rhamnose, hydroxykynurenic acid, kynurenic acid, protocatechuic acid, vanillic acid, shikimic acid, d-glucaric acid, ginkgolic acid, and related alkylphenols have also been isolated. Seeds of G. biloba contain ginkgotoxins, which can induce epileptic seizures, and the phenolic type lipid bilobol, which has cytotoxic properties.

5. Mechanisms of Action

Antioxidant and free radical scavenging. Flavonoids are known to act as major antioxidants among various polyphenols and also act as heavy metal chelators due to their phenolic structures. GBE is a powerful antioxidant that prevents free radicals from damaging cellular membranes, an effect that has been found to be especially beneficial in brain and nerve cells.

Platelet-activating factor (PAF) antagonism. Ginkgolides have been specifically shown to act as platelet-activating factor (PAF) antagonists, inhibiting platelet aggregation and stimulating blood flow. Although PAF antagonism is primarily attributed to the terpene fraction, the flavone glycosides and terpene lactones work synergistically in the whole extract. Its mechanisms — PAF inhibition, free radical scavenging, and cerebral vasodilation — collectively improve the delivery and utilisation of oxygen and glucose in brain tissue.

Neuroprotective and antiapoptotic mechanisms. EGb 761 interferes with pathomechanisms relevant to dementia, such as Aβ aggregation, mitochondrial dysfunction, insulin resistance, and hypoperfusion. Its broad spectrum of pharmacological activities allows it to address numerous pathological requirements — hemodynamic, hemorheological, metabolic — which occur in cerebral, retinal, cochleovestibular, cardiac or peripheral ischemia; moreover, EGb 761 has direct effects against necrosis and apoptosis of neurons and improves neural plasticity as evidenced in vestibular compensation.

Cardiovascular and vasoactive effects. GBE and isolated ginkgolides have been shown to inhibit platelet aggregation, adhesion, and degranulation and to improve cardiac contractility and coronary blood flow; these actions appear to be due to ginkgo's direct membrane and antioxidant effects, increased synthesis of prostacyclin, and other mechanisms.

GFG-specific contributions in ischemia. In a myocardial ischemia–reperfusion injury (MIRI) model, pretreatment with GFGs at 2.5 ml/kg was superior to the same dose of ginkgolides in improving cardiac function and coronary blood flow and reducing the levels of lactate dehydrogenase and aspartate aminotransferase in serum. Network pharmacology analysis of GFGs and GGs revealed the tumor necrosis factor-related weak inducer of apoptosis (TWEAK)–fibroblast growth factor-inducible 14 (Fn14) signaling pathway as an important common mechanism but with differential targets in myocardial and cerebral ischemia–reperfusion injury.

Neurotransmission modulation. Effects include modulation of neurotransmission, memory-boosting effects, inhibition of apoptosis, antioxidant and anti-inflammatory effects, enhancement of neurogenesis, increase in cerebral blood flow, and improvement in cognitive function. Recent studies show anxiolytic properties of ginkgolide A, migraine with aura treatment by ginkgolide B, a reduction in ischemia-induced glutamate excitotoxicity by bilobalide, and an alternative antihypertensive property of quercetin, among others.

Synergistic actions of the whole extract. The neuroprotective properties of Ginkgo biloba, including antioxidants, anti-apoptotic, anti-inflammatory, and vasoregulatory mechanisms, are attributed to its extract components; the synergistic activity of these chemicals in Ginkgo biloba activates various molecular pathways, including neuronal survival, cerebral perfusion, and synaptic plasticity.

6. Scientific Evidence by Area of Use

6.1 Cognitive Function, Dementia, and Alzheimer's Disease

This is the most extensively studied application of ginkgo flavone glycoside-containing extracts in humans.

Overview of clinical trial program. The efficacy of EGb 761 in the treatment of dementia (Alzheimer's disease and vascular dementia) has been studied in 10 randomized, controlled, double-blind clinical trials. In three of the four large trials conducted in accordance with recent recommendations, EGb 761 was significantly superior to placebo with respect to cognitive performance and one or more further (global, functional, or behavioural) outcomes demonstrating the clinical relevance of the findings; the findings from the six smaller trials are in line with those of the large trials.

Systematic review and meta-analysis (2015). A 2015 systematic review and meta-analysis involving a total of 2,561 participants concluded that Ginkgo biloba EGb-761 at 240 mg/day stabilized or slowed decline in cognition, function, behavior, and global change at 22 to 26 weeks in cognitive impairment and dementia, especially for people with neuropsychiatric symptoms.

Meta-analysis in Alzheimer's disease (2020). A 2020 meta-analysis of 7 randomized controlled trials involving 939 patients with Alzheimer's disease found that those given Ginkgo biloba extract EGb-761 had some improvement in cognitive function; treatments varied within the studies from 120, 160, and 240 mg/day, and duration ranged from 3 months to 26 weeks.

Meta-analysis of placebo-controlled trials (2014). Seven of 15 randomized, placebo-controlled trials in patients with dementia identified by database searches met all selection criteria and were included in the meta-analysis; in these trials, patients were treated with 120 mg or 240 mg per day of the defined extract EGb 761 or placebo. Standardized mean differences for change in cognition (−0.52; 95% CI −0.98, −0.05; P=0.03), activities of daily living (−0.44; 95% CI −0.68, −0.19; P<0.001), and global rating (−0.52; 95% CI −0.92, −0.12; P=0.01) significantly favored EGb 761 compared with placebo; statistically significant superiority of EGb 761 over placebo was confirmed by responder analyses as well as for patients suffering from dementia with neuropsychiatric symptoms.

The GOTADAY / GINDEM-NP / GOT-IT! trials. The GINDEM-NP, GOTADAY, and GOT-IT! studies showed that 240 mg/day EGb 761® improved cognitive function, neuropsychiatric symptoms, activities of daily living, and quality of life in patients with mild to moderate dementia compared with placebo, with results reproducible in independent trials; the strength of the effect in terms of improvements in neurosensory symptoms associated with old age and dementia was strong enough to be detected by caregivers and independent clinicians.

24-week double-blind RCT (intent-to-treat analysis). After 24 weeks of treatment, the intent-to-treat (ITT) analysis revealed a mean decrease in the total SKT score by −2.1 points and estimated ADAS-cog scores by −2.7 points for the EGb 761 group, indicating an improvement in cognitive function; the placebo group exhibited only a minimal change of −1.0 and −1.3 points, respectively; the changes from baseline differed significantly between treatment groups (P = 0.01).

Mild cognitive impairment (MCI). In those with mild cognitive impairment (MCI), EGb 761® has demonstrated significant symptomatic improvement versus placebo. Gavrilova and colleagues (2014) evaluated EGb 761® (240 mg/day) versus placebo for 24 weeks in 160 patients with amnesic MCI (age >55 years); all neuropsychiatric symptoms, measured through the Neuropsychiatric Inventory (NPI), improved in patients treated with EGb 761®; they reached a better diagnosis also for anxiety, depression, and visual-motor and cognitive aspects.

Guideline endorsement. World Federation of Societies of Biological Psychiatry guidelines list EGb 761® with the same strength of evidence as acetylcholinesterase inhibitors and NMDA antagonists.

NCCIH / NIH position. There is no conclusive evidence that Ginkgo biloba is efficacious in preventing or slowing dementia or cognitive decline; a large, placebo-controlled, randomized clinical trial studying the well-characterized ginkgo product EGb-761 in more than 3,000 older adults found it ineffective in lowering the overall incidence of dementia and Alzheimer's disease; further analysis of the same data also found ginkgo to be ineffective in slowing cognitive decline, lowering blood pressure, or reducing the incidence of hypertension. This large trial (the Ginkgo Evaluation of Memory [GEM] Study) thus stands in contrast to several smaller and shorter European trials showing symptomatic benefits, representing the ongoing debate over the clinical meaningfulness of the observed effects.

Evidence strength: Moderate. Meta-analyses of RCTs using EGb 761 at 240 mg/day for 22–26 weeks demonstrate statistically significant but modest improvements in cognition, activities of daily living, and global function in patients with existing mild-to-moderate dementia and neuropsychiatric symptoms. The evidence for prevention of dementia in healthy older adults is negative based on the GEM study. Evidence for MCI is promising but limited by fewer trials.

6.2 Tinnitus and Neurosensory Symptoms

There is evidence of efficacy for the standardized extract EGb 761® in the treatment of tinnitus from three trials in patients in whom tinnitus was the primary complaint; supportive evidence comes from a further five trials in patients with age-associated cognitive impairment or dementia in whom tinnitus was present as a concomitant symptom; as yet, the efficacy of other ginkgo preparations has not been proven, which does not necessarily indicate ineffectiveness but may be due to flawed clinical trials.

Ginkgo is frequently marketed for tinnitus (ringing in the ears), but a Cochrane review examining four trials with 1,543 total participants found no evidence that ginkgo is effective when tinnitus is the primary complaint.

For tinnitus patients without cardiovascular disease, a recent systematic review and a meta-analysis have both reported that Ginkgo biloba does not show higher efficacy than placebo, with an exception in elderly patients with dementia.

A randomized, double-blind trial compared EGb 761® (120 mg twice daily) with pentoxifylline (600 mg twice daily) over 12 weeks in patients with subchronic or chronic tinnitus. The full analysis set comprised 197 patients (EGb 761®: 99; pentoxifylline: 98); for both treatment groups, significant improvements were observed in the Mini-Tinnitus Questionnaire (Mini-TQ), the 11-point box scales for tinnitus loudness and annoyance, the HADS anxiety score, and the Sheehan Disability Scale. The therapy appears to be particularly beneficial for patients with normal hearing and/or concomitant anxiety and/or stress.

Evidence strength: Weak-to-moderate and inconsistent. EGb 761® may reduce tinnitus severity as a secondary symptom in dementia/MCI patients. For tinnitus as a primary standalone condition, the current body of evidence, including a Cochrane review, does not support efficacy.

6.3 Peripheral Arterial Disease and Intermittent Claudication

A WHO monograph indicates the use of G. biloba extract for symptomatic treatment of mild to moderate cerebrovascular insufficiency, improvement of pain-free walking distance in patients with peripheral arterial occlusive disease (PAOD), and treatment of inner ear problems like tinnitus.

For peripheral arterial disease, a systematic review and a meta-analysis have both reported that Ginkgo biloba shows higher efficacy than placebo for treating intermittent claudication. However, later Cochrane analysis was more cautious: fourteen trials with a total of 739 participants were included; eleven trials involving 477 participants compared Ginkgo biloba with placebo and assessed the absolute claudication distance (ACD); following treatment with Ginkgo biloba, the ACD increased with an overall effect size of 3.57 kilocalories (CI −0.10 to 7.23, P=0.06) compared with placebo, translating to an increase of just 64.5 (CI −1.8 to 130.7) metres on a flat treadmill. Publication bias leading to missing data or "negative" trials is likely to have inflated the effect size; overall, there is no evidence that Ginkgo biloba has a clinically significant benefit for patients with peripheral arterial disease.

Evidence strength: Weak. While some meta-analyses reported statistically significant improvements in claudication distances, the Cochrane review found the absolute effect size to be small and the evidence potentially biased by publication effects. The clinical significance of the observed magnitude of benefit is uncertain.

6.4 Cardiovascular Disease Prevention

The GEM Study, the largest randomized trial of EGb 761, addressed cardiovascular endpoints. The double-blind trial randomized 3,069 participants over age 75 to 120 mg of EGb 761 twice daily or placebo; mean follow-up was 6.1 years. There were 355 deaths in the study, 87 due to coronary heart disease with no differences between G. biloba and placebo; there were no differences in incident myocardial infarction (n=164), angina pectoris (n=207), or stroke (n=151) between G. biloba and placebo. For hypertension, a recent systematic review has shown that there is no convincing evidence to support the efficacy of extracts of Ginkgo biloba as an anti-hypertensive, due to the flawed study design and poor methodological quality of most randomized clinical trials assessed.

Evidence strength: Negative for prevention. The largest and longest RCT found no reduction in major cardiovascular events (MI, stroke, coronary heart disease death) with long-term EGb 761 use in older adults.

6.5 Cardioprotection and Cerebral Ischemia–Reperfusion Injury

EGb has a broad range of pharmacological effects, such as anti-inflammation, antioxidant, anti-apoptotic, antidepressant, anti-arrhythmia, antitumor, improving cognitive function, and relieving ischemia–reperfusion injury. In contrast to GFGs' superiority in myocardial protection, pretreatment with ginkgolides at 2.5 ml/kg reduced cerebral infarction area and cerebral edema similarly to that of SXNI but more significantly compared with GFGs in the cerebral ischemia–reperfusion injury model.

Evidence strength: Largely preclinical (animal models) for ischemia–reperfusion. Clinical RCT data in this specific area remain limited; most available data arise from in vitro and animal studies, with some observational and open-label human data from injectable preparations used in East Asia.

6.6 Anxiety and Depression

Recent studies show anxiolytic properties of ginkgolide A; among the flavonoid aglycones, quercetin exhibits antihypertensive properties. In dementia trials, neuropsychiatric symptom improvements including anxiety and depression have been observed. EGb 761® has shown convincing results improving cognitive function, neuropsychiatric symptoms, and consequent reduction of caregiver stress and maintenance of autonomy in patients with age-related cognitive decline, MCI, and mild to moderate dementia.

Evidence strength: Preliminary for standalone anxiety and depression. Most supportive data derive from subgroup analyses within dementia trials, not from primary anxiety or depression trials.

7. Body Systems and Health Areas of Association

Central nervous system: Cognitive function, memory, dementia (Alzheimer's and vascular), mild cognitive impairment, neuropsychiatric symptoms (anxiety, depression, agitation).
Cerebrovascular system: Cerebral blood flow, ischemia–reperfusion injury, cerebrovascular insufficiency.
Cardiovascular system: Peripheral arterial disease (intermittent claudication), cardiac ischemia–reperfusion, coronary blood flow, platelet aggregation inhibition.
Sensory organs: Tinnitus and dizziness (vestibular/cochlear), as secondary outcomes in dementia patients.
Respiratory system: Historically used in TCM for asthma, bronchitis, and cough (seed preparations).
Immune and inflammatory pathways: Antioxidant, anti-inflammatory, and heavy metal chelating actions of flavonoid glycosides.

In the last decades, Ginkgo biloba has been used clinically for the prevention and treatment of different cardiovascular diseases, including hypertension, cerebrovascular disease, peripheral arterial disease, peripheral venous disease, Raynaud's phenomenon, and erectile dysfunction; in addition, this plant has also been used in diseases with a probable underlying vascular dysfunction component, such as cognitive decline, dementia, and tinnitus.

8. Dosage Forms and Doses Reported in Studies

EGb 761 is standardized to include 6% terpenoids and 24% flavonoid glycosides; standard dosages of EGb 761 used in most studies and recommended by manufacturers are 40 mg three times per day, or 80 mg twice daily.

The standard clinical dose of EGb 761 is 120 mg (~1.7 mg/kg) once or twice daily; thus, a standard dose will contain approximately 3–4 mg ginkgolides A, B, and C, 3–4 mg bilobalide, and 29 mg flavonoids.

In the dementia meta-analysis, patients were treated with 120 mg or 240 mg per day of the defined extract EGb 761 or placebo. In the 2015 systematic review addressing cognitive decline, the effective dose was 240 mg/day, with treatment duration of 22 to 26 weeks. The GEM prevention trial used 120 mg of EGb 761 twice daily (i.e., 240 mg/day) over a mean follow-up of 6.1 years. In the tinnitus comparison trial, the dose was 120 mg EGb 761® twice daily over a 12-week period.

Based on the glycoside, maximum plasma concentrations of flavonol conjugates may be reached within 30 minutes or only after several hours, yielding completely different pharmacokinetic profiles. A study on healthy persons after oral and intravenous administration of EGb 761 that contained 24% flavonoids and 6% terpenoids reflected their bioavailability; the absolute bioavailabilities of ginkgolides A and B were greater than 80%, and ginkgolide C indicated very low bioavailability after oral intake of 80 mg of EGb 761; however, oral intake of 120 mg of EGb 761 resulted in 70% bioavailability of bilobalide.

9. Safety Considerations and Drug Interactions

General tolerability. In general, Ginkgo biloba is safe and well-tolerated. Treatment-associated risks in terms of relative risks of adverse events and premature withdrawal rates did not differ noticeably between the EGb 761 and placebo groups; meta-analyses confirmed the efficacy and good tolerability of EGb 761 in patients with dementia.

Bleeding risk and anticoagulant/antiplatelet interactions. Ginkgo may increase the risk of bleeding in people who are taking anticoagulant drugs, such as warfarin. The evidence from controlled studies, however, is complex and nuanced: some writers hold the view that the combination of Ginkgo biloba with anticoagulant or antiplatelet drugs represents a serious health risk; such concerns are largely based on the assumption that ginkgo has clinically relevant antiplatelet activity, as well as accounts of bleeding episodes associated with ginkgo consumption; however, results from controlled studies consistently indicate that ginkgo does not significantly impact haemostasis nor adversely affect the safety of co-administered aspirin or warfarin.

Although the potential bleeding risk of Ginkgo biloba has been much discussed in the literature, initial concerns were based on case reports describing a temporal association between ginkgo use and bleeding events; some evaluations of randomized controlled trials have not found a higher bleeding risk; a systematic review and meta-analysis of 18 randomized controlled trials looked at the impact of ginkgo on haemostasis parameters associated with bleeding risk and found a significant reduction in blood viscosity, but there were no effects on other factors, such as ADP-induced platelet aggregation, fibrinogen concentration, activated partial thromboplastin time, and prothrombin time.

A 2025 retrospective observational study examining 2,647 prescriptions found: Ginkgo biloba extract exhibited drug interactions with a prevalence rate of 12.94%; notably, ginkgo extract frequently interacts with antiplatelets, anticoagulants, and nonsteroidal anti-inflammatory drugs, with clopidogrel and aspirin exhibiting the highest prevalence rates of 2.61% each. Interactions with anticoagulants including direct oral anticoagulants and acenocoumarol were not statistically significant in that analysis.

Ginkgolic acid (allergen). Individuals with a history of strong allergic reactions to poison ivy, mangoes, cashews, and other alkylphenol-producing plants are more likely to experience an allergic reaction when consuming non-standardized ginkgo-containing preparations; the level of these allergens in standardized pharmaceutical preparations from Ginkgo biloba was restricted to 5 ppm by the Commission E of the former Federal German Health Authority.

Seed toxicity — ginkgotoxin. Seeds of G. biloba contain ginkgotoxins, which can induce epileptic seizures. Overconsumption of seeds from Ginkgo biloba can deplete vitamin B6. These toxic seed constituents are not present in the standardized leaf extracts used in supplements and pharmaceuticals.

Pregnancy and lactation. Ginkgo may be unsafe for use during pregnancy; it might cause early labor or extra bleeding during delivery if used near that time; little is known about whether it's safe to use ginkgo while breastfeeding.

Other drug interactions. Ginkgo may also interact with other drugs. The 2025 observational study identified specific interactions: omeprazole was a frequently interacting drug (2.34%) of mild severity. The mechanism of a potential blood pressure interaction has also been noted: ginkgo can lower blood pressure via vasodilation and PAF inhibition, and combined with antihypertensive medications, this may produce additive blood pressure lowering.

References

Health Conditions

Health conditions that Ginkgo flavone glycoside may help support.

Neuropathy & Nerve HealthScientific
Ginkgo flavone glycosides are the principal polyphenolic antioxidant fraction of standardized Ginkgo biloba extract (EGb 761), comprising flavonoid glycosides of quercetin, kaempferol, and isorhamnetin. They protect peripheral nerve cell membranes from oxidative damage and contribute to microcirculatory improvements supporting peripheral nerve perfusion, with relevance to neuropathy management.

Body Systems

Body systems that Ginkgo flavone glycoside may help support.

No body systems available.