IngredientsBotanical source. Ginkgolides are biologically active terpenic lactones present in Ginkgo biloba. They are diterpenoids with 20-carbon skeletons, which are biosynthesized from geranylgeranyl pyrophosphate. Ginkgo biloba L. (family Ginkgoaceae) is the sole living representative of an ancient gymnospermous lineage and is sometimes called a "living fossil." Ginkgolides are diterpenoid trilactone-containing unique C20 lactone cage molecules that are the main principles from the slow-growing Ginkgo biloba L. (especially from the leaf part), which is from a gymnospermous tree, a species in the division Ginkgophyta, and a single surviving species.
Unique occurrence in nature. Ginkgolides, as one of the main active ingredients in Ginkgo biloba leaves, are a rare class of natural compounds that have not been found in other plants so far. They are the only known natural products possessing a tert-butyl group as part of their core structure. One exception has been noted: aside from the G. biloba tree, ginkgolide A has also been reported to be present in Machilus wangchiana.
Known members of the ginkgolide family. Ginkgolides are mainly divided into ginkgolides A, B, C, J, K, L, and M. In 1967, Nakanishi reported several compounds found in Ginkgo biloba extract, among which four diterpene lactones with special structures were first reported from this plant, namely ginkgolides A, B, C, and M. Ginkgolides A, B, C, M, and J are diterpene lactone compounds that were separated from ginkgo leaves by S. Furukawa in 1932 for the first time, and were further separated and their chemical structures determined by K. Nakanishi, M. Maruyama, and K. Okabe in 1967. Two additional trace compounds were later identified as ginkgolide K and ginkgolide L.
Core architecture. Ginkgolides, which are C20 diterpenes, consist of six five-membered rings — a spiro[4,4]nonane carbocyclic ring, three lactones, and a tetrahydrofuran. The molecular skeleton of the peculiar ginkgolide is small and the carbon skeleton in the molecule is highly functionalized. The whole molecule is a twisted cage structure.
Structural differentiation among analogs. Ginkgolides A, B, C, M, and J are structurally different in the number of hydroxyls and positions of connecting the hydroxyls. Ginkgolide A (GA) is a diterpene which has two secondary hydroxyl groups on C1 and C10 containing no hydroxyl substitution in the 2-position compared to other ginkgolides. Its molecular formula is C20H24O9 and its molecular weight is 408.399 Da.
Biosynthetic origin. Five multifunctional cytochrome P450s with atypical catalytic activities generate the tert-butyl group and one of the lactone rings, characteristic of all G. biloba trilactone terpenoids. The reactions include scarless C–C bond cleavage as well as carbon skeleton rearrangement (NIH shift) occurring on a previously unsuspected intermediate. The cytochrome P450s involved belong to CYP families that diversified in pre-seed plants and gymnosperms but are not preserved in angiosperms — offering a glimpse into the biosynthesis of terpenoids of the Mesozoic Era.
Relationship to bilobalide. Ginkgolides co-occur in the leaf with bilobalide, a sesquiterpenoid (C15) lactone. Ginkgolide preparations comprise diterpene lactones and sesquiterpene lactones: the diterpene lactones mainly include ginkgolides A, B, C, J, and M, and the sesquiterpene lactones include bilobalide. While bilobalide shares the trilactone scaffold, it possesses a 15-carbon backbone and is structurally distinct from the ginkgolides proper.
Composition in the standardized extract EGb 761. The chemical constituents of EGb 761 are evaluated as follows: 22–27% of flavone glycosides, 2.8–3.4% of ginkgolide A, B, and C, 2.6–3.2% of bilobalide, and less than 5 ppm of ginkgolic acid. 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.
Chinese medicine. 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. Ginkgo trees have a long history of use in traditional Chinese and Japanese cooking and medicine to treat conditions such as asthma, cough, and enuresis.
The Ben Cao Gang Mu (Compendium of Materia Medica). Researchers have reviewed the 16th-century Chinese text, the Ben Cao Gang Mu by Li Shi-Zhen, to investigate the ancient prescription of ginkgo seeds for skin infections. The Ben Cao Gang Mu is a collection of previous annotations and summarized over 40 earlier pharmacopeia and more than 300 medical texts. In total, 17 traditional uses were reported in the book, including 8 for skin disorders such as chapped hands and feet, rosacea, patches and nodules on the face and scalp, genital ulcers, crab louse-induced itchiness, dog bite wound abscess, mastitis, and bullae or pustules. In the methods of preparation, Li Shi-Zhen mentioned applying the paste of raw ginkgo kernels to the affected area, or rubbing sliced-open raw kernels on it.
Respiratory and digestive uses. Besides respiratory applications, the Chinese acknowledged the potential of Ginkgo biloba seeds to tackle digestive issues and conditions related to bladder health. Consistent and widespread usage across these domains underscored the cultural and therapeutic importance of Ginkgo biloba, making it a crucial element in Chinese traditional medicine.
Introduction to the West and modern standardization. The advent of Ginkgo biloba in Western countries occurred much later, with its first documentation appearing in the 17th century by European botanists who began to take interest in its unique characteristics. Initially, its adoption in Europe was primarily ornamental. Over time, Ginkgo biloba's medicinal properties sparked further investigation, and by the latter half of the 20th century, research into its health benefits led to heightened interest, resulting in a considerable rise in its utilization. Its seeds have been used as snacks and medical materials in traditional Chinese medicine, while over the last century its leaf extracts emerged as a source of rising pharmaceutical commerce related to brain health in Western medicine.
Note: Traditional records document the use of the whole plant (seeds, leaves) and whole-plant preparations. Ginkgolides as chemically defined entities were not isolated until the 20th century. Their specific contributions to traditional therapeutic effects were thus unknown to historical practitioners, who used ginkgo preparations containing a full spectrum of phytochemicals.
Ginkgolides are all platelet-activating factor antagonists, and a key ingredient of special physiological activity in ginkgo leaves. Platelet-activating factor (PAF) is a phospholipid originally discovered as an IgE-sensitized rabbit basophil-derived substance responsible for platelet aggregation. The cellular effects of PAF are mediated by a specific G-protein-coupled receptor (PAFR). It is known that ginkgolides, particularly ginkgolide B (GB), are strong antagonists of the PAFR.
Among the ginkgolide compounds, the unique 20-carbon cage molecules have been shown to specifically inhibit PAF-induced actions such as platelet aggregation, hypotension, and bronchoconstriction, and to exert a protective effect in experimentally induced diseases such as brain ischemia and eye inflammation.
Potency ranking. PAF-mediated aggregation of human platelets was half-maximally inhibited by ginkgolide B, A, C, and J at concentrations of 2.5, 15.8, 29.8, and 43.5 µg/mL, respectively. Ginkgolide C is 25-fold less potent than ginkgolide B as a PAF receptor antagonist, due to the presence of the 7β-OH.
Mechanism at the receptor level. Studies indicate that the compound (ginkgolide B / BN 52021) inhibits neutrophil responses to PAF by inhibiting binding of PAF to its specific neutrophil receptor. BN 52021 over the range of 10⁻⁹–10⁻⁴ M inhibited PAF-induced degranulation and superoxide production of PMNLs in a dose-dependent manner.
Ginkgolides are antagonists of the inhibitory ligand-gated ion channels for the neurotransmitters glycine and gamma-aminobutyric acid (GABA). Ginkgolides A, B, C, and J were classified as blockers of glycine-activated receptors. Ginkgolides were proved to block the open chloride channel of glycine-activated receptors. Further research demonstrated that the effect of ginkgolides depends on their concentration. Ginkgolides act as non-competitive antagonists towards glycine-activated receptors.
Both ginkgolides and bilobalide inhibit GABA(A) receptors, with bilobalide demonstrating a more potent effect. There is evidence that open channels are required for glycine receptor inhibition by ginkgolides. Molecular modeling demonstrates a striking similarity between ginkgolides and picrotoxinin, a GABA(A) and recombinant glycine alpha-homomeric receptor antagonist.
Alzheimer's disease studies have shown that ginkgolides inhibit both NMDAR (N-methyl-D-aspartate receptor) and AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor). Through PAF antagonism and modulation of glutamate receptor activity, ginkgolides are associated with reduced excitotoxic neuronal injury.
Ginkgolides have antioxidant, anti-inflammatory, anti-platelet aggregation, anti-apoptotic, anti-cell death, and vasodilatory pharmacological effects and can also protect the central nervous system and ischemic tissue. In ischemic stroke research, many studies have shown that the increase of SIRT1 expression, the suppression of NF-κB, the inhibition of the PI3K/Akt pathway and TLR4/NF-κB, the up-regulation of heme oxygenase 1, erythropoietin secretion and anti-apoptotic protein expression, the inhibition of pro-apoptotic proteins, and the improvement of endothelial NO synthesis are the main molecular mechanisms involved in the protective effect of ginkgolide B on ischemic stroke.
New molecular targets of ginkgolide B identified in research include nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidase), lectin-like oxidized LDL receptor-1 (LOX-1), sirtuin 1 (SIRT1), platelet-activating factor (PAF), and proprotein convertase subtilisin/kexin type 9 (PCSK9).
Ginkgolide B significantly increased the Bcl-2/Bax ratio, reduced the expression of caspase-3, and protected against OGD/R-induced neuronal apoptosis. GB also caused the up-regulation of BDNF protein in vivo and in vitro, suggesting that GB might protect the brain against ischemic insult partly via modulating BDNF expression.
Clinical evidence overview. Ginkgo biloba (GB) contains bioactive compounds such as terpenoids (ginkgolides A, B, and C), polyphenols, organic acids, and flavonoids. These compounds are associated with anti-inflammatory, antioxidant, and neuroprotective properties, making them valuable for cognitive health. A systematic search across three databases using specific keywords — GB in Alzheimer's disease (AD) and dementia — yielded 1,702 documents, leading to the selection of 15 clinical trials for synthesis. In eleven studies, GB extract/EGb 761® was shown to improve cognitive function, neuropsychiatric symptoms, and functional abilities in both dementia types. In four studies, however, there were no significant differences between the GB-treated and placebo groups.
Outcome measures. Significant improvements were observed in scores obtained from the Mini-Mental State Examination (MMSE), Short Cognitive Performance Test (SKT), and Neuropsychiatric Inventory (NPI).
Overview of systematic reviews. Across a 2016 overview of ten systematic reviews, medication with GBEs showed improvement in cognition, neuropsychiatric symptoms, and daily activities, and the effect was dose-dependent. Efficacy was convincingly demonstrated only when a high daily dose (240 mg) was applied.
Meta-analysis quantitative findings. A meta-analysis showed statistically significant differences in several outcomes including mean difference in MMSE score (3.02, 95% CI 2.14–3.89, P < 0.00001), Activity of Daily Living Scale score (−4.56, 95% CI −5.09 to −4.03, P < 0.00001), and Montreal Cognitive Assessment score (2.38, 95% CI 0.72–4.06, P = 0.005) between experimental and control groups.
Mechanistic basis in AD. Ginkgolide B, one of the major active ingredients in EGb, can inhibit the neurotoxicity induced by β-amyloid. Findings suggest that ginkgolide B alleviates AD-induced cognitive deficits by attenuating oxidative stress, neuroinflammation, and ferroptosis.
Evidence quality assessment. Whether EGb improves cognitive function in clinical studies is a controversial question. Although a few available large-scale clinical trials suggest that EGb is relatively efficacious in delaying the progress of dementia, several other trials showed negative results. Ginkgo biloba is potentially beneficial for the improvement of cognitive function, activities of daily living, and global clinical assessment in patients with mild cognitive impairment or Alzheimer's disease. However, due to limited sample size, inconsistent findings, and methodological quality of included trials, more research is warranted.
Preclinical evidence. Investigators examined the effect of the known PAF antagonist ginkgolide B on post-ischemic neuronal damage in the rat. Neuronal necroses were evaluated in the hippocampus 7 days after a 10-minute forebrain ischemia. Preischemic application of ginkgolide B (50 mg/kg p.o.) significantly reduced neuronal damage, and it is suggested that the antagonism of PAF is responsible for this beneficial effect.
GB treatment (4 mg/kg, i.p., bid) significantly reduced neurological deficits, water content, and cerebral infarct volume in transient middle cerebral artery occlusion (tMCAO) mice. GB also significantly increased Bcl-2/Bax ratio and reduced the expression of caspase-3.
Clinical trial — GIANT study. A total of 1,113 patients were included and 513 (46.1%) were in the intervention group. Patients in the Ginkgolide® group were more likely to have good outcomes (78.6% vs. 66.7%, P < 0.01) and a lower rate of symptomatic intracerebral hemorrhage (0 vs. 2.72%, P < 0.01) compared with patients in the control group. The conclusion of this multicenter cluster-randomized trial was that using Ginkgolide® within 24 hours after IV rt-PA is effective and safe and might be recommended in combination with rt-PA therapy in acute ischemic stroke.
Systematic review and meta-analysis. A meta-analysis of five trials on ginkgo diterpene lactone meglumine injection combined with rt-PA thrombolytic therapy for acute ischemic stroke showed that combination therapy was better in improving clinical efficacy (OR = 1.91, 95% CI 1.13–3.22, P = 0.02) and neurological function (MD = −3.31, 95% CI −3.64 to −2.98, P < 0.001). Importantly, no serious adverse drug reactions or events were reported.
Evidence quality. Most stroke research involving ginkgolide preparations has been conducted in Asian populations and often uses injectable formulations (ginkgo diterpene lactone meglumine injection, GDLMI) not available in Western markets. The evidence is promising but the clinical trial base is less extensive than that for standard stroke therapies, and most trials have been conducted in China.
Recent studies show migraine with aura treatment as an application of ginkgolide B specifically. Clinical results describing efficacy of ginkgo extract constituents for the treatment of migraine have been described, for example to prevent migraine in adolescents 8–18 years using 2 × 80 mg ginkgolide B over 3 months; for prophylaxis in women with migraine with aura using 2 × 60 mg ginkgo terpenes for 3 months; and for the treatment of acute migraine with aura in men and women using 2 × 60 mg/d ginkgo terpenes at the onset of the migraine attack.
Evidence quality. Various studies have researched the effect of ginkgo biloba on migraines, but there is a lack of strong evidence. A 2009 study in Italy showed a decrease in migraine attacks, although the study had its limits (no placebo group). Current evidence in this area is preliminary and derived from small studies, several of which lack placebo controls.
Preclinical studies have shown that ginkgolide B, a bioactive component in Ginkgo biloba, can ameliorate atherosclerosis in cultured vascular cells and disease models. 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 ischemia. Ginkgolide B, the primary ingredient of some Ginkgo biloba extracts, possesses cardioprotective properties, such as protection of cardiomyocytes against doxorubicin-induced cardiomyocyte damage.
Evidence quality. Cardiovascular evidence is primarily preclinical (cell and animal models) with limited clinical trial data. No large controlled trials in Western populations have demonstrated cardiovascular benefit for ginkgolides in isolation.
In a pilot study involving 104 patients, not testing whole G. biloba extract but ginkgolide B at 240 mg or 360 mg/d or placebo over only 7 days, a trend for improvement in multiple sclerosis (MS) patients was observed compared to placebo. This was a single pilot study by Brochet et al. (1995); evidence in multiple sclerosis remains exploratory and preliminary.
Recent research has highlighted ginkgolide B's potential antitumor effects, including the induction of apoptosis, cell cycle arrest, and angiogenesis inhibition, by modulating critical signaling pathways such as PI3K/Akt, MAPK, and NF-κB. Additionally, ginkgolide B has demonstrated the ability to enhance the efficacy of conventional chemotherapeutic agents, suggesting its potential as an adjunct therapy in cancer treatment.
Ginkgolide B has a strong antagonistic ability against platelet-activating factor and is the strongest compound in nature that specifically antagonizes PAFR. In the concentration range where ginkgolide B does not produce cytotoxicity, gemcitabine in combination with ginkgolide B can enhance the effect of gemcitabine in killing resistant pancreatic cancer cells by inhibiting the PAFR/NF-κB pathway and reduce the resistance of pancreatic cancer to gemcitabine.
Evidence quality. Anticancer evidence is derived primarily from in vitro cell-line studies and animal models. No human clinical trials have established ginkgolides as a stand-alone cancer therapy. One study on lung cancer that circulated in the literature was subsequently retracted. Results must be viewed as preclinical and hypothesis-generating only.
Ginkgo trees have a long history of use in traditional Chinese and Japanese medicine to treat conditions such as asthma and cough. The ginkgolides have been shown to specifically inhibit PAF-induced bronchoconstriction. A completed NCCIH-funded clinical trial (NCT00029679, 2000–2005) examined borage oil and EGb 761 in asthma, though final results from this trial are not fully reported in the public literature. Evidence for anti-asthmatic efficacy of ginkgolides in humans remains limited and inconclusive.
EGb 761 (the standardized extract). The most extensively studied preparation, EGb 761, is a dried, standardized extract of Ginkgo biloba leaves. It contains approximately 24% flavone glycosides (primarily quercetin, kaempferol, and isorhamnetin) and about 6% terpenoid lactones (2.8–3.4% ginkgolides A, B, C, and 2.6–3.2% bilobalide) as its main active components, along with other constituents such as proanthocyanidins and organic acids.
Oral tablet and capsule forms. 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. Medication with GBEs showed improvement in cognition, neuropsychiatric symptoms, and daily activities, and efficacy was convincingly demonstrated only when the high daily dose of 240 mg was applied.
Injectable ginkgo diterpene lactone meglumine injection (GDLMI). This preparation, used in China and studied in the GIANT trial and related systematic reviews, contains concentrated ginkgolide constituents administered intravenously in acute stroke settings. Meta-analysis examined five trials on ginkgo diterpene lactone meglumine injection combined with rt-PA thrombolytic therapy. This formulation is not generally approved in Western regulatory jurisdictions.
Isolated ginkgolide B for migraine. In migraine prophylaxis trials, the following specific dosages were used: 2 × 80 mg ginkgolide B over 3 months in adolescents (8–18 years); 2 × 60 mg ginkgo terpenes for 3 months for prophylaxis in women with migraine with aura; and 2 × 60 mg/d ginkgo terpenes at the onset of the migraine attack for acute migraine with aura.
Isolated ginkgolide B for MS pilot trial. A pilot study tested ginkgolide B at 240 mg or 360 mg/d over only 7 days in 104 MS patients.
Preclinical rodent dose context. Preischemic application of ginkgolide B at 50 mg/kg p.o. significantly reduced neuronal damage in rat forebrain ischemia models. In tMCAO mice, GB treatment at 4 mg/kg i.p. twice daily significantly reduced neurological deficits, water content, and cerebral infarct volume. These animal doses are not directly translatable to human dosing.
The question of whether ginkgolides or EGb 761 increase bleeding risk has been extensively studied. The evidence is more nuanced than commonly presented. PAF-mediated aggregation of human platelets was half-maximally inhibited by ginkgolide B, A, C, and J at concentrations of 2.5, 15.8, 29.8, and 43.5 µg/mL, respectively. These concentrations are generally more than 100 times higher than the peak plasma values measured after oral intake of EGb 761 at recommended doses between 120 and 240 mg. As PAF is a "weak" platelet activator, these results raise serious doubts that the PAF antagonistic effect of ginkgolides could be responsible for hemorrhage in patients taking EGb 761.
Results from controlled studies consistently indicate that Ginkgo does not significantly impact hemostasis nor adversely affect the safety of coadministered aspirin or warfarin. Most of these studies were undertaken using EGb 761, a well-defined extract of Ginkgo biloba. EGb 761 has not generally been implicated in the case reports of bleeding. In general, the quality of these case reports is low. Nevertheless, the possibility of an idiosyncratic bleeding event due to ginkgo use cannot be excluded on the basis of the available information.
In a secondary analysis of a randomized placebo-controlled trial, no evidence was found that EGb 761® affects hemostasis or increases the bleeding risk. No pharmacodynamic interactions with warfarin or acetylsalicylic acid were found.
Results from controlled studies revealed that none of the 29 coagulation and bleeding parameters evaluated showed any evidence of EGb 761 inhibiting blood coagulation or platelet aggregation. However, out of 2,647 prescriptions meeting inclusion criteria in a retrospective observational study, 342 exhibited drug interactions, with a prevalence rate of 12.94%. Notably, Ginkgo biloba extract frequently interacts with antiplatelets, anticoagulants, and nonsteroidal anti-inflammatory drugs, with clopidogrel and aspirin exhibiting the highest prevalence rates of 2.61% each.
A study has concluded that ginkgolide A can induce the CYP1A2 enzyme, though not as much as other chemicals present in ginkgo. This means that ginkgolide A can increase the action of CYP1A2. Some researchers have ascribed potential pharmacokinetic interactions with warfarin based on research on hepatocytes showing that ginkgo induced the cytochrome P450 3A4 enzyme, which may affect the R enantiomer of warfarin.
G. biloba leaves and sarcotesta contain ginkgolic acids — which are highly allergenic. 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.
Ginkgo seeds (not leaves/extracts) contain 4'-O-methylpyridoxine, a neurotoxic compound distinct from ginkgolides. Standardized leaf extracts such as EGb 761 are processed to remove or limit this and other undesirable constituents.
In a meta-analysis of randomized clinical trials of ginkgo terpene lactone preparations for ischemic stroke, no serious adverse drug reactions or adverse drug events were reported. Of observed bleeding events in the EGb 761 Alzheimer's trial, the majority occurred in patients who took at least one concomitant drug with known anticoagulant side effects. Only eight patients in EGb 761 groups were affected by bleeding events for whom no concomitant anticoagulant drug exposure was documented; in six of them, evident other causes such as invasive cancer or fall-related injuries were present and were not assessed as causally related to the study medication.
Health conditions that Ginkgolides may help support.
Ginkgolides are unique diterpene lactones found exclusively in Ginkgo biloba and form part of the active terpene fraction of standardized ginkgo extract. Ginkgolide B is a potent platelet-activating factor (PAF) antagonist, contributing to improved cerebral blood flow and neuroprotection. Their inclusion in standardized EGb 761 extracts underpins the cognitive benefits documented in RCTs.
Ginkgolides are terpene lactone constituents of standardized Ginkgo biloba extract (2.8–3.4% ginkgolides A, B, C) that contribute to its neuroprotective and cognitive effects. Ginkgolide B specifically inhibits platelet-activating factor and β-amyloid neurotoxicity. Their activity is documented within the context of EGb 761 clinical trials showing memory improvements in mild cognitive impairment and Alzheimer's disease.
Ginkgolide B, a terpene from Ginkgo biloba, has been studied for migraine with aura prophylaxis. An open multicenter trial in 50 women found significant reductions in aura frequency and duration over 4 months. Ginkgolide B acts as a platelet-activating factor (PAF) antagonist and modulates glutamate in the CNS, mechanisms relevant to migraine aura.
Body systems that Ginkgolides may help support.
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