Ginkgoside

Ginkgosides: A Comprehensive Encyclopedic Reference

1. Identity and Nomenclature

1.1 Botanical Source and Common Names

Ginkgosides — used as a collective informal term in the supplement literature to refer to the biologically active glycoside and terpenoid constituents of Ginkgo biloba L. — are derived exclusively from a single plant species: Ginkgo biloba, the sole surviving member of the family Ginkgoaceae and the order Ginkgoales. Commonly known as the ginkgo or maidenhair tree, G. biloba is a species of gymnosperm native to East Asia and the last living species in the order Ginkgoales, which first appeared over 290 million years ago. Because of its extraordinary longevity and taxonomic isolation, the plant is often called a "living fossil," the leading surviving member of the Ginkgoaceae family, which appeared approximately 250 million years ago.

In Chinese traditional medicine the tree is known as Bái guǒ (白果, "white fruit") referring to the seed, and Yín xìng yè (银杏叶) referring to the leaf. The standardized English common name for the supplement ingredient is "ginkgo," with the pinyin names yin xing (tree), bai guo (seed), and yin xing ye (leaf).

The term "ginkgoside" does not correspond to a single, well-defined chemical entity in pharmacopeial or biochemical literature; rather, it is a broadly applied informal descriptor. In rigorous scientific and pharmacopeial usage the relevant constituent classes are distinguished as flavonol glycosides (also called ginkgo flavone glycosides or flavoglycosides) and terpene trilactones (the ginkgolides and bilobalide). The main pharmacologically active compounds in G. biloba are flavonol glycosides and terpene tri-lactones (bilobalide and ginkgolides). A number of specific novel glycosides isolated from ginkgo tissues have been given individual names by researchers; for example, one novel neolignan glucoside, Ginkgoside B, along with a new glucose ester were isolated from the ethanol extract of Ginkgo biloba leaves, and a phytochemical analysis of G. biloba fruit identified six phenylpropanoid glycosides, including one new compound designated ginkgopanoside.

1.2 Natural Source and Plant Part

Ginkgo biloba L. of the Ginkgoaceae family is a deciduous tree growing 20–40 meters in height, native to eastern China. Ginkgo has a long history of use in Chinese medicine for treating cough, diarrhea, and other conditions; today, ginkgo leaf — usually as an extract — is the most commonly used form of ginkgo. While the seeds were historically the primary medicinal material, the leaf is the source of all commercially significant phytochemical preparations today.

1.3 Common Forms and Preparations

Commercial preparations of ginkgo fall into several categories:

• Standardized dry leaf extract (EGb 761): The standardized preparation of Ginkgo biloba leaf extract made from dried green leaves, named EGb 761, contains two main bioactive constituents — flavonoid glycosides (approximately 24%) and terpene lactones (ginkgolides and bilobalide, approximately 6%) — along with less than five ppm of the allergenic component ginkgolic acid. This extract is sold under trade names including Tanakan®, Tebonin®, and Rokan®. In 1964, an extract of Ginkgo leaves (EGb 761) was introduced into Western medical practice.
• Dried powdered leaf: The dried, powdered leaves are sometimes used in supplements, although virtually all clinical studies have used standardized extracts.
• Concentrated leaf extract (non-standardized): Extracts prepared with varying solvents, yielding differing phytochemical profiles. DNA was detected in all ginkgo leaf extracts, but the highest levels of phytochemicals were obtained using ethanol or acetone as solvents.
• Traditional seed preparations: The nut-like kernels of the seeds are esteemed in Asia and are a traditional ingredient in Chinese food; ginkgo nuts are used in congee and are often served at special occasions such as weddings and the Chinese New Year.

The extraction process concentrates the active compounds to approximately 50 times the concentration found in the raw leaf, and also removes impurities including heavy metals and potentially toxic ginkgolic acids.

2. Traditional and Historical Use

2.1 China

Ginkgo was first recorded as a medicinal plant in the Chinese Materia Medica Shen Nong Ben Cao Jing approximately 2,000 years ago, and only the seeds were reported to be used as medicine at that time. Ginkgo has been used in traditional Chinese medicine since at least the 11th century CE. Ginkgo seeds, leaves, and nuts have traditionally been used to treat various ailments, such as dementia, asthma, bronchitis, and kidney and bladder disorders.

Much later, the leaves of G. biloba were cited for the treatment of heart and lung diseases in traditional Chinese medicine, and this part of the plant attracted most attention from outside China. A 16th-century Chinese text, the Ben Cao Gang Mu by Li Shi-Zhen, contains ancient prescriptions of ginkgo seeds for skin infections.

2.2 Japan and Korea

Japanese cooks add ginkgo seeds (called ginnan) to dishes such as chawanmushi, and cooked seeds are often eaten along with other dishes. In the Edo period (1600–1867), common people began to eat ginkgo seeds as a vegetable and as an ingredient in pickles. In the 18th century the nuts became used as a side dish when drinking sake. Phytopharmaceutical extracts from the leaves of Ginkgo biloba have been applied to treat cerebrovascular and peripheral vascular diseases in countries such as Germany, France, Japan, and Korea since the 1960s.

2.3 Western Introduction

Western medicine began to look at the use of ginkgo in the 1950s. Toward the end of the 20th century, ginkgo extract became popular in many countries for its purported memory-enhancing properties. For a long time, Ginkgo biloba has been used as a herbal medicine not only in China but also in the United States and Europe for various diseases; concentrated and partly purified products have been marketed widely under different trade names for the treatment and management of cognitive deficiencies, other age-related impairments, and many chronic and acute diseases such as cardiovascular and bronchial pathologies.

3. Key Constituents and Active Compounds

3.1 Overall Phytochemical Composition

Ginkgo extract contains over 60 bioactive ingredients, but the most important role is played by flavonoids and terpenoids, which usually constitute about 24% and 6% of the extract, respectively. Moreover, it contains organic acids, proanthocyanidins, tannins, sitosterols, carotenoids, polysaccharides, glucose, and other ingredients including minerals and vitamins.

3.2 Flavonol Glycosides (Ginkgo Flavone Glycosides)

Flavonoids frequently present in Ginkgo leaf extract include flavones, biflavones (bilobetol, amentoflavone, 5-methoxybilobetol, ginkgetin, isoginkgetin, and sciadopitysin), flavonols, tannins, and glycosides of quercetin and kaempferol. The standardized extract from ginkgo leaves — EGb 761 — contains 24% flavonoids, mainly flavonol O-glycosides including quercetin, kaempferol, isorhamnetin, and proanthocyanidins.

Among all these compounds, flavone glycosides and flavonol glycosides — which include kaempferol, quercetin, and isorhamnetin with glucose or rhamnose — are the most emphasized in Ginkgo biloba extracts on the market; experiments have demonstrated that flavone glycosides and flavonol glycosides are potent antioxidants that scavenge oxygen free radicals, thereby preventing age-related cell and tissue damage that can adversely affect various mental functions including memory and concentration.

The standardized commercial extracts of G. biloba leaf used in ginkgo supplements contain not less than 6% sesquiterpene lactones and 24% flavonol glycosides; while sesquiterpene lactones are unique constituents of ginkgo leaf, the flavonol glycosides are found in many other botanical extracts.

3.3 Terpene Trilactones: Ginkgolides and Bilobalide

Only two types of terpenoids are found in ginkgo leaf: ginkgolides and bilobalide. Ginkgolides are diterpene trilactones with five types (A, B, C, J, and M), while bilobalide is a unique sesquiterpene trilactone. So far, G. biloba is the only known source of ginkgolide A, B, C, M, J, and K.

Ginkgolides are twenty-carbon cage molecules incorporating a t-butyl group and six five-membered rings, including a spiro[4.4]nonane, a tetrahydrofuran cycle, and three lactone rings; the various ginkgolide structures differ only by the number and position of hydroxyl groups on the C1, C3, or C7 of the spirononane framework.

The standardized extract of Ginkgo biloba leaves (GBE) contains 6% terpenoids (in which 3.1% are ginkgolides A, B, C, and J and 2.9% is bilobalide) and 24% flavonoid glycosides; other constituents such as glucose, rhamnose, hydroxykynurenic, kynurenic, protocatechuic, vanillic, and shikimic acids, d-glucaric acid, ginkgolic acid, and related alkylphenols have also been isolated.

While flavonol glycosides are the most abundant, terpene lactones are unique to ginkgo and are believed to have the ability to cross the blood–brain barrier due to their lipophilic character, thus being capable of acting on the central nervous system.

3.4 Ginkgolic Acids and Other Constituents

Ginkgo also contains terpene trilactones (ginkgolides), acylated flavonol glycosides (ginkgoghrelins), biflavones (ginkgetin), ginkgotides, and ginkgolic acids. Ginkgolic acids are phenolic lipids primarily present in the seed and fruit coat and represent a potential allergenicity concern; commercial extracts specifically limit their presence (see Safety section).

4. Mechanisms of Action

4.1 Antioxidant and Free Radical Scavenging

The flavoglycosides present in ginkgo are considered its most active components and have shown significant pharmacological capacities; these chemical compounds have free radical scavenging properties and act as antioxidant agents, and consist of kaempferol, isorhamnetin, and quercetin. Flavonoids are known to act as major antioxidants among various polyphenols and also act as heavy metal chelators due to their phenolic structures.

4.2 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. One of the components of Ginkgo biloba, ginkgolide B, is a potent platelet-activating factor (PAF) antagonist. The terpene substances of ginkgo — incorporating the ginkgolides and the bilobalides — help reduce inflammation by inhibiting platelet-activating factor (PAF) in the blood; this activity facilitates reinforcement of circulation, and PAF plays a role in various diseases such as heart attacks, strokes, atherosclerosis, and asthma.

4.3 Neuroregulatory and Neurotransmitter Modulation

Ginkgolides present a wide variety of neuroregulatory properties commonly associated with diseases such as Alzheimer's, Parkinson's, and many other CNS-related diseases and disorders; the neuroregulative properties of ginkgolides include the conditioning of neurotransmitter action, e.g., glutamate or dopamine; they additionally induce the inhibition of platelet-activating factors (PAF) and influence the inflammatory process.

Following oral administration of GBE, significant levels of terpene trilactones and G. biloba flavonoids cross the blood–brain barrier and enter the CNS of rats, a characteristic that suggests G. biloba can have a positive impact on neurological disorders.

4.4 Vascular and Circulatory Effects

Ginkgolides have been clinically shown to act as platelet-activating factor (PAF) antagonists, inhibiting platelet aggregation and promoting increased blood flow; flavonoids are known to act as antioxidants and heavy metal chelators due to their phenolic structures and have been clinically investigated in cardiovascular and inflammatory diseases. In addition, studies have examined ginkgo's capacity to modulate nitric oxide production — a key endothelial vasodilatory mechanism — as a supplementary pathway through which it may influence blood flow.

4.5 Anti-inflammatory Properties

Ginkgo extracts possess antioxidant, antineuro-inflammatory, anti-asthmatic, and wound-healing properties. There is substantial experimental evidence to support the view that ginkgo biloba extracts have neuroprotective properties under conditions such as hypoxia/ischemia, seizure activity, and peripheral nerve damage. Although the terpene fraction of Ginkgo biloba, which contains the ginkgolides, may contribute to the neuroprotective properties of the ginkgo leaf, the flavonoid fraction — containing free radical scavengers — is also likely important in this respect.

5. Scientific Evidence by Area of Use

5.1 Cognitive Decline, Dementia, and Alzheimer's Disease

This is the most extensively researched therapeutic area for ginkgo preparations and the evidence here is nuanced, distinguishing between treatment of existing cognitive decline and prevention of future decline in healthy individuals.

Prevention of Dementia in Healthy Older Adults:

In three large studies in older adults with normal cognitive function or mild cognitive impairment, supplementation with ginkgo extract did not reduce the risk of dementia. One of these studies was the Ginkgo Evaluation of Memory (GEM) study, funded by the National Center for Complementary and Integrative Health and the National Institute on Aging, in which more than 3,000 people age 75 or older with normal cognitive function or mild cognitive impairment were randomly assigned to take a ginkgo supplement or a placebo for a median of 6 years; there was no difference between the ginkgo and placebo groups in the rates at which participants developed dementia of any type or Alzheimer's disease. In this study, participants received a twice-daily dose of 120 mg extract of G. biloba, and the extract at 120 mg twice a day was not effective in reducing either the overall incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI.

Treatment of Existing Dementia or Cognitive Impairment:

Ginkgo extract may have a modest benefit for dementia symptoms, particularly at relatively high doses, but the evidence is inconsistent; it is unclear whether ginkgo is helpful for symptoms of milder cognitive impairment.

A meta-analysis found that EGb761 at 240 mg/day is able to stabilize or slow decline in cognition, function, behavior, and global change at 22–26 weeks in cognitive impairment and dementia, especially for patients with neuropsychiatric symptoms; safety data revealed no important safety concerns with EGb761.

The effects of EGb 761 on cognition were dose-dependent; at the higher daily dose of 240 mg, EGb 761 showed a significantly better overall effect on cognition than placebo. Seven of 15 randomized, placebo-controlled trials in patients with dementia 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.

A 24-week, multicenter, double-blind, randomized, placebo-controlled trial with 410 outpatients examined EGb 761® at 240 mg once-daily in patients with mild to moderate dementia (Alzheimer's disease or vascular dementia) associated with neuropsychiatric symptoms. Patients treated with EGb 761® improved by 2.2 ± 3.5 points (mean ± SD) on the SKT total score compared to placebo.

From four eligible trials, data of 782 patients with mild dementia were included in a meta-analysis; the analysis demonstrated that treatment with 240 mg EGb 761 daily was significantly superior to placebo in cognition (p=0.04), global assessment (p=0.01), activities of daily living (p=0.01) and quality of life (p=0.02) with medium to large standardized effects.

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.

The pooled analyses from a systematic review provide evidence of efficacy of EGb 761® at a daily dose of 240 mg in the treatment of outpatients suffering from Alzheimer's, vascular, or mixed dementia with behavioral and psychological symptoms of dementia (BPSD).

Notwithstanding these positive signals in established dementia patients, the overall regulatory and systematic review position remains cautious. The National Center for Complementary and Integrative Health (NCCIH) of the National Institutes of Health (NIH) stated that there is no conclusive evidence that Ginkgo biloba extract is helpful to improve or prevent cognitive decline. The evidence that ginkgo has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unconvincing.

A review concluded that EGb may be able to improve cognitive function in patients who suffered from mild dementia during long-term administration of more than 24 weeks at an appropriate dosage of 240 mg per day.

Evidence strength: Moderate-to-mixed. Large trials do not support dementia prevention in healthy older adults. For treatment of mild-to-moderate dementia — particularly with neuropsychiatric features — some meta-analyses of standardized EGb 761 at 240 mg/day report statistically significant benefit across cognition, activities of daily living, and global change at 22–26 weeks, but the clinical significance and consistency across trials remain debated.

5.2 Tinnitus and Dizziness

In earlier clinical trials, Ginkgo biloba extract EGb 761® was found to alleviate tinnitus and dizziness in elderly patients; consequently, a meta-analysis was conducted to evaluate the effects of EGb 761® at a daily dose of 240 mg on tinnitus and dizziness associated with dementia.

In Germany and other countries, medicinal products containing EGb 761® — the dried extract of Ginkgo biloba leaves — as an active substance are approved for the symptomatic or adjuvant treatment of patients with tinnitus of vascular or involutive origin.

A double-blind, randomized trial enrolled patients with sub-chronic or chronic tinnitus. Patients were randomized to receive 120 mg EGb 761® or 600 mg pentoxifylline, each twice a day and in double-dummy fashion over a 12-week period. For both treatment groups, significant improvements were observed in the Mini-TQ, the 11-Point Box Scales for tinnitus loudness and annoyance, the HADS anxiety score, and the SDS; there was no relevant difference with regard to tinnitus-related outcomes between the two treatment groups.

An open-label, exploratory, multicenter study enrolled 170 patients with chronic tinnitus. The study took 120 mg EGb 761® twice daily for 24 weeks and assessed outcomes using the Tinnitus Questionnaire and Tinnitus Handicap Inventory; at week 24, significant improvements were observed in all tinnitus-related outcomes compared to baseline (all p < 0.0001). In subgroup analyses, patients with high baseline anxiety or stress as well as those with normal hearing improved more, whereas baseline depression had no influence; the overall response rate was 18.8%.

A mediation analysis pooled data from three double-blind, randomized, placebo-controlled clinical trials. These trials investigated the efficacy of EGb 761® (240 mg/day for 22–24 weeks) in dementia with concomitant neuropsychiatric symptoms; in total, 594 patients suffered from tinnitus (EGb 761®, 289; placebo, 305).

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.

Evidence strength: Moderate for tinnitus associated with dementia in elderly patients at 240 mg/day, supported by multiple randomized controlled trials and meta-analyses. Evidence for standalone tinnitus without dementia is weaker and inconsistent — systematic reviews report no superiority over placebo in this population.

5.3 Peripheral Artery Disease and Intermittent Claudication

Ginkgo biloba has been used clinically for the prevention and treatment of different cardiovascular diseases, including peripheral arterial disease and peripheral venous disease. Ginkgo biloba extract, derived from the leaves of the ginkgo tree, has been used in traditional Chinese medicine for centuries and is a vasoactive agent believed to have a positive effect on walking ability in patients with peripheral arterial disease.

Ginkgo has been used for reducing pain while walking in people with intermittent claudication — a condition caused by peripheral artery disease — and some early clinical trials showed modest increases in pain-free walking distance; the typical dose studied for this indication was 120–240 mg/day of standardized ginkgo extract. However, the magnitude of benefit in available trials has been small, and larger, higher-quality trials are lacking; the evidence is considered insufficient to recommend ginkgo over established treatments for peripheral vascular disease.

Overall, there is no evidence that Ginkgo biloba has a clinically significant benefit for patients with peripheral arterial disease, according to the Cochrane Collaboration systematic review.

Evidence strength: Weak to insufficient. Despite a plausible pharmacological rationale based on PAF antagonism and vasodilation, the Cochrane review found no clinically significant benefit for intermittent claudication.

5.4 Cardiovascular and Cerebrovascular Applications

Ginkgo biloba is a well-known traditional Chinese medicine with notable cardiovascular actions, used as a cardio- and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries; preclinical studies have shown that ginkgolide B can ameliorate atherosclerosis in cultured vascular cells and disease models, and several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases such as ischemic stroke.

For hypertension, a recent systematic review has shown that there is no convincing evidence to support the efficacy of Ginkgo biloba extracts as an anti-hypertensive, due to flawed study design and poor methodological quality of most randomized clinical trials assessed.

For Raynaud's disease, different results have been reported in double-blind placebo-controlled clinical trials: one trial reported that EGb could be effective in reducing the frequency of vascular attacks, whereas another reported that EGb did not reduce the duration and severity of attacks compared with placebo; additionally, another clinical study showed that Ginkgo biloba was inferior to nifedipine in the treatment of primary Raynaud's disease.

Evidence strength: Preliminary to mixed for cardiovascular indications. Preclinical data are promising for ginkgolide B in atherosclerosis; human clinical evidence for hypertension and Raynaud's disease is inconsistent and of low-to-moderate quality.

5.5 Psychiatric and Neuropsychiatric Symptoms

In clinical trials, EGb 761® treatment decreased the severity of anxiety in patients with anxiety disorders or dementia and reduced symptoms of depression in patients with mild cognitive impairment or dementia, irrespective of the absence or presence of tinnitus.

Even though some clinical trials show positive results in the neuropsychiatric area, the majority of systematic reviews and meta-analyses have shown less encouraging evidence overall.

Evidence strength: Preliminary to moderate, particularly for anxiety and depression as secondary symptoms in dementia patients receiving EGb 761 at 240 mg/day. Evidence in primary psychiatric diagnoses without dementia is substantially weaker.

6. Dosage Forms and Reported Dosages

The following dosages reflect those reported in identified peer-reviewed clinical studies and should be understood only as study dosages, not as personal recommendations:

• 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 dementia trials, patients were treated with 120 mg or 240 mg per day of the defined extract EGb 761 or placebo.
• A multicenter 24-week trial used a 240 mg once-daily formulation of EGb 761® in patients with mild to moderate dementia.
• Three pooled placebo-controlled clinical trials investigated the efficacy of EGb 761® at 240 mg/day for 22–24 weeks in dementia.
• A tinnitus trial used 120 mg EGb 761® twice a day (240 mg/day total) in double-dummy fashion over a 12-week period.
• An open-label tinnitus study enrolled patients who took 120 mg EGb 761® twice daily for 24 weeks.
• The GEM prevention trial used a twice-daily dose of 120 mg extract (240 mg/day total).
• The typical dose studied for intermittent claudication was 120–240 mg/day of standardized ginkgo extract.

7. Body Systems and Health Areas of Association

Ginkgo biloba has been used clinically in 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, it has been used in diseases with a probable underlying vascular dysfunction component, such as cognitive decline, dementia, and tinnitus.

• Central nervous system: Cognitive function, memory, dementia (Alzheimer's disease, vascular dementia, mixed dementia), mild cognitive impairment, neuropsychiatric symptoms (anxiety, depression in dementia), Parkinson's disease (preclinical and early clinical).
• Auditory and vestibular systems: Tinnitus (especially in elderly patients with dementia), dizziness, vertigo of vascular or involutive origin.
• Cardiovascular and peripheral vascular systems: Peripheral arterial disease, intermittent claudication, Raynaud's phenomenon, cerebrovascular disease (ischemic stroke), atherosclerosis.
• Respiratory system: Asthma and bronchitis were traditional indications for ginkgo seeds and leaves.
• Urogenital system: Kidney and bladder disorders were traditional indications.
• Antioxidant/anti-inflammatory: Systemic antioxidant activity attributed to flavonol glycosides; anti-inflammatory effects relevant to multiple organ systems.

8. Safety Considerations and Drug Interactions

8.1 General Safety Profile

Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo; many of the early trials used unsatisfactory methods, were small, and publication bias cannot be excluded. Safety data from meta-analyses of EGb761 revealed no important safety concerns.

8.2 Bleeding Risk and Anticoagulant/Antiplatelet Interactions

Ginkgo may increase the risk of bleeding in people who are taking anticoagulant drugs such as warfarin, and may also interact with other drugs.

Although the potential bleeding risk of Ginkgo biloba has been much discussed in the literature, initial concerns were based on case reports that described a temporal association between ginkgo use and bleeding events; some evaluations of randomized controlled trials have not found a higher bleeding risk. Results from controlled studies consistently indicate that ginkgo does not significantly impact haemostasis nor adversely affect the safety of co-administered aspirin or warfarin.

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

Significant correlations were found between Ginkgo biloba extract drug interactions and bleeding risk (OR: 1.08, p < 0.001) and abnormal coagulation (OR: 1.49, p < 0.001).

8.3 Ginkgotoxin and Seizure Risk

Ginkgotoxin, which induces epileptic seizures, is found in G. biloba seeds. In epileptic patients or in patients prone to seizure, physicians should be cautious with the administration of ginkgo, as ginkgo toxin — mostly found in ginkgo seeds but still present in ginkgo leaves — could lower the seizure threshold.

Ginkgo might increase the risk of seizures in people with epilepsy and reduce the effectiveness of anti-seizure drugs; the mechanism may involve ginkgotoxin (4'-O-methylpyridoxine), a naturally occurring compound in ginkgo that can inhibit GABA synthesis; while the amount in standardized extracts is small, this interaction is clinically significant for people with seizure disorders.

Ginkgo seeds contain 4′-O-methylpyridoxine (ginkgotoxin), which can precipitate seizures, especially in children or people with low vitamin B6 status; standardized leaf extracts used in supplements contain negligible ginkgotoxin.

8.4 Cytochrome P450 and Drug Metabolism Interactions

Ginkgo biloba can affect hepatic drug metabolism through the cytochrome P450 system; ginkgo may induce CYP3A4, potentially reducing plasma levels of drugs metabolized by this enzyme (e.g., some statins, calcium channel blockers, immunosuppressants).

8.5 Blood Glucose Interactions

Ginkgo can alter blood glucose levels and may interfere with responses to insulin, metformin, sulfonylureas, and other glucose-lowering agents; patients with diabetes who take ginkgo should monitor blood glucose more frequently.

8.6 Ginkgolic Acid and Allergenicity

The standardized preparation EGb 761 limits the allergenic component ginkgolic acid to less than five ppm. Ginkgolic acids present in unprocessed leaf material and seed coats have cytotoxic and allergenic potential, and the extraction process used to prepare EGb 761 specifically reduces their concentration.

8.7 Seed Toxicity

Raw ginkgo seeds are toxic and can cause seizures, loss of consciousness, and death — particularly in children; even roasted ginkgo seeds can cause adverse reactions in some individuals.

8.8 Regulatory Actions

Over the period of 2021–2023, the US FDA issued warning letters to manufacturers of ginkgo dietary supplements for false advertising about health claims and misbranding of their products as non-approved drugs.

8.9 Product Adulteration

Only three of the commercially available ginkgo finished products tested in one study were determined to be authentic, with flavonol glycoside rutin and aglycones quercetin, kaempferol, and isorhamnetin found to be common adulterants in ginkgo powdered extract and finished product samples. In another authentication study, 4 out of a total of 19 plant food supplement samples were adulterated, with two samples evidencing the addition of quercetin from sources other than ginkgo.

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