Abstract
EGb 761® (Tanakan®) is a standardized extract of Ginkgo biloba leaves that has demonstrated protective properties against neuronal and vascular damage. Overall, in randomized, placebo-controlled clinical trials and meta-analyses in adults with mild-to-moderate dementia, EGb 761® displayed positive effects, with changes from baseline in outcomes related to cognition, behaviour and global change that are generally better than those shown with placebo. EGb 761® is generally well tolerated, with no safety issues being identified during its many years of widespread use.
Similar content being viewed by others
Standardized pharmaceutical-quality extract |
Has a range of neuroprotective effects, including acting as a potent antioxidant and scavenger of free radicals |
Has a positive impact on the symptoms, including cognitive impairment, of mild-to-moderate dementia in adults |
Generally well tolerated, with no safety issues |
What is the rationale for using EGb 761® in mild-to-moderate dementia?
Dementia is a chronic or progressive condition that is characterized by impaired cognitive capacity and dependency on others, the severity of which is greater than that considered a consequence of normal aging [1]. Common forms of dementia include Alzheimer’s disease (AD) and vascular dementia (VD), which affect many aspects of neurological function, including memory, thinking, orientation, comprehension, learning ability and judgement. The molecular pathogenesis of dementia of the AD type is complex and likely to involve several factors [1]. The most important of these are thought to be the effects of oxidative stress, abnormal formation and aggregation of the β-amyloid protein (Aβ), hyperphosphorylation of the tau protein, and changes in the cholinergic system involving glutamatergic neurotransmission alterations [1, 2].
Treatment options for patients with dementia are limited [3]. Acetylcholinesterase inhibitors (AChEIs) may improve cognitive function in some patients with mild-to-moderate dementia, but current drug therapies cannot cure or prevent its progression [1, 3]. In recent years, the interest in developing natural plant-derived compounds for the treatment of cognitive decline has increased [4]. The Ginkgo biloba tree is the source of one such agent, with extracts from the leaves having been widely used for their health promoting properties for many decades [4, 5]. EGb 761® (Tanakan®) is a standardized extract of Ginkgo biloba leaves that has demonstrated protective properties against neuronal and vascular damage [4, 5]. Other Ginkgo biloba extracts (many as herbal dietary supplements) have been marketed over the years. [6, 7]. As these extracts are not standardized to the specifications used in the formulation of EGb 761®, they are not considered pharmaceutically equivalent to EGb 761® [6, 7].
For whom is EGb 761® indicated?
EGb 761® is approved throughout Europe for the symptomatic treatment of adults with cognitive impairment and mild-to-moderate dementia [8, 9]. Table 1 summarizes the use of EGb 761® in this indication in Europe [based on the Czech [8] and Lithuanian [9] summaries of product characteristics (SPCs)]. The use of EGb 761® to treat other conditions is beyond the scope of this review. Consult local information for further details.
How does EGb 761® work?
EGb 761® has numerous pharmacological actions that derive from the various constituents of the herbal extract, acting separately or synergistically [5, 10,11,12]. The most pharmacologically important constituents in the treatment of cognitive decline are the flavonoid glycosides and terpene trilactones [5, 10].
Neuroprotective effect
Various mechanisms are associated with the neuroprotective effect of EGb 761®, including free radical-scavenging, antioxidant effects, improvement in mitochondrial function, regulation of neurotransmitters, and effects on neuronal plasticity (Table 2) [5, 10, 11]. In addition, preliminary results with EGb 761® in adults with memory impairment suggest mild enhancement of prefrontal dopamine [13].
EGb761® improved learning and memory and had a beneficial effect on age-related behaviour in animals, as well as being associated with improvements in memory in healthy volunteers (Table 2).
Effects on lesions associated with Alzheimer’s disease
EGb 761® was associated with protective activity against Aβ-induced neurotoxicity [14]. Aβ is involved in the pathogenesis of AD and is the main constituent of amyloid plaques found in the brains of AD patients [2, 15]. In addition, studies indicate that EGb 761® induces amyloid precursor protein metabolism toward α-secretase pathway, preventing the formation of Aβ peptides [16].
In vitro and in vivo studies indicate that EGb 761® protects against Aβ-induced neurotoxicity by blocking the pathological cascade of Aβ-induced events, including reactive oxygen species generation and mitochondrial dysfunction, as well as dose-dependently protecting against Aβ-induced apoptosis and neurotoxicity (Table 2) [10].
What is the pharmacokinetic profile of EGb 761®?
After oral administration of EGb 761® in humans, the flavonoid glycosides and terpene trilactones reach the CNS in measurable concentrations [17]. The terpene trilactones, including A and B ginkgolide and bilobalide, reach maximum plasma concentrations within 1–2 h and are characterized by relatively short half-lives (Table 1). By 24 h after administration, terpene trilactones cannot be detected in the brain [17]. The half-life of the flavonoids contained in EGb 761® is about 10–17 h [17]. Because of the relatively short half-lives of the active constituents, EGb 761® should be taken more than once daily (Table 1) [8, 9, 17].
What is the efficacy of EGb 761® in mild-to-moderate dementia?
Compared with placebo
Numerous studies have evaluated Ginkgo biloba extracts in the treatment of AD and/or VD. This section focuses on the primary/co-primary endpoint-related results in the intent-to-treat (ITT) populations of randomized, controlled trials (RCTs) of EGb 761® 120–240 mg/day in divided doses (as per the recommended regimen) versus placebo in the symptomatic treatment of mild-to-moderate AD and/or VD [46,47,48,49,50,51,52,53,54,55,56,57,58], and meta-analyses [59,60,61,62,63] of these [46,47,48,49,50,51, 53,54,55,56,57,58] and other RCTs [64, 65]. Only the key results of fully-published RCTs in a total of > 100 patients [46,47,48,49,50,51, 53,54,55,56,57,58] and recent meta-analyses (i.e. published in 2013 or onwards) [59,60,61,62,63] are discussed. The diagnostic criteria for dementia varied between RCTs, which may have affected trial outcomes.
In the total populations, where reported, the proportion of patients who discontinued treatment before the end of the 22–26 week trials was generally comparable between the EGb 761® 120–240 mg/day and placebo groups (2–28 vs 2–23%) [46, 47, 50, 51, 53, 55, 57].
Cognition
In RCTs with primary cognition-related endpoints, EGb 761® was significantly more effective than placebo in improving cognition as measured by changes from baseline in Syndrom-Kurz test (SKT; a psychometric test that assesses memory and attention) scores in most [47, 53, 56], but not all [51, 58] of the RCTs that assessed this outcome (Table 3). In subgroup analyses of these RCTs in patients with AD [47, 55, 57] and/or VD [55, 57], changes from baseline in SKT scores also significantly favoured EGb 761® over placebo (Table 3). Likewise, cognition, as assessed by changes from baseline in Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) scores, decreased to a significantly lesser extent with EGb 761® than with placebo at 52 weeks in one RCT (Table 3) [49].
There were no significant treatment differences (TDs) in ADAS-cog scores in the overall population of two other RCTs [46, 50] that assessed this outcome. However, in the subgroup of patients with NPS in one of these RCTs [46], changes from baseline in ADAS-cog scores significantly favoured EGb 761® 240 mg/day over placebo (Table 3). Likewise, although there was no significant difference between EGb 761® 120 or 240 mg/day and placebo with regard to the proportion of patients with AD who showed an improvement or no change in their condition as assessed by the Alzheimer’s Disease Cooperative Society Clinical Global Impression of Change scale (ADCS-CGI) [46], ADCS-CGI scores significantly favoured EGb 761® 120 mg/day over placebo in the NPS subgroup (Table 3) [46]. The other RCT that showed no significant TDs in ADAS-cog scores [50] has been criticized for being under powered [66]. In the two RCTs that assessed the global change in cognition using the Clinical Global Impression (item 2) [CGI-2] scale, EGb 761® 160–240 mg/day was significantly more effective than placebo [47, 51].
In the ITT population in one RCT [47], the proportion of patients who responded to treatment (defined as a decrease from baseline in ADAS-cog scores of ≥ 2 or 4 points) was determined by estimating ADAS-cog scores based on measured SKT scores. Significantly more EGb 761® 240 mg/day recipients than placebo recipients were ≥ 2-point responders (61 vs 37%; p < 0.001) and ≥ 4-point responders (35 vs 19%; p = 0.01) in the overall population. Corresponding results in the subgroup of patients with AD were comparable (66 vs 34%; p < 0.001) and (35 vs 19%; p = 0.02) [47].
EGb 761® 240 mg/day was significantly (p < 0.01) more effective than placebo with regard to mean changes from baseline/screening in secondary cognition-related outcomes in the overall populations and the subgroups of patients with AD and/or VD in some trials [i.e. Verbal Fluency Test (VFT) [53,54,55,56,57], Test for Early Detection of Dementia with Discrimination from Depression (TE4D) cognitive score [53] and Clock Drawing Test (CDT) [56, 57]]. However, there were no significant differences between EGb 761® 160/240 mg/day and placebo with regard to changes from baseline in test scores used to assess trail-making speed, digit memory span and verbal learning [52].
Activities of daily living
In the 52-week trial [48], the ability to perform activities of daily living (ADL), as assessed by changes from baseline in Geriatric Evaluation by Relative’s Rating Instrument (GERRI) scores, improved to a significantly greater extent with EGb 761® 120 mg/day than with placebo. However, there were no significant differences between EGb 761® (160/240 [51] or 240 mg/day [47]) and placebo in other RCTs that assessed changes from baseline in ADL using the Nürnberger-Alters-Beobachtungs-Skala (NAB) [47] or Nürnberger-Alters-Alltagsaktivitäten-Skala (NAA) [51] as a co-primary endpoint (Table 3).
In the overall populations and the subgroups of patients with AD or VD, EGb 761® 240 mg/day was significantly (p < 0.01) more effective than placebo with regard to the secondary endpoints of changes from baseline in AD-ADL International scale (ADL-IS) [53,54,55] and Gottfries-Bråne-Steen (GBS)-ADL scores [56, 57] in some trials. EGb 761® 160/240 mg/day was more effective than placebo with regard to changes from baseline in self-perceived ADL, but not when data were corrected for confounding [52].
Behaviour and other outcomes
As assessed by Neuropsychiatric Inventory (NPI) scores as a primary endpoint in RCTs in patients with neuropsychiatric symptoms (NPS), EGb 761® 240 mg/day was significantly more effective in improving behaviour than placebo in all [53,54,55] but one [58] RCT that assessed this outcome (Table 3).
With regard to secondary outcomes, EGb 761® 240 mg/day was significantly (p < 0.05) more effective than placebo with regard to the mean change from baseline in behaviour-related outcomes (NPI [56, 57] and NPI caregiver distress score [53,54,55,56,57]) in patients with dementia [56] (including the subgroups of patients with AD or VD [57]) and patients with dementia with NPS [53, 54] (including the subgroups of patients with AD or VD [55]) in the RCTs that evaluated these outcomes. There were no significant differences between EGb 761® 160/240 mg/day and placebo with regard to changes from baseline in geriatric symptom, depressive mood, and self-perceived health and memory status scores [52].
Changes from baseline in health-related quality-of-life (HR-QOL), as assessed by participant-rated Quality of Life in AD scores, did not differ to a statistically significant extent between EGb 761® 120 mg/day and placebo in the single RCT in which this was a co-primary endpoint (Table 3) [50]. In the overall populations and the subgroups of patients with AD or VD in some trials, EGb 761® 240 mg/day was significantly (p < 0.03) more effective than placebo with regard to the mean change from baseline in secondary global change outcomes (ADCS-CGIC [53,54,55]) and HR-QOL (DEMQOL-Proxy total score in the total [53,54,55] and AD (but not VD) populations [55]) and GBS overall geriatric assessment scale [56, 57].
Meta-analyses
Meta-analyses (which included most of the RCTs in Table 3 and/or other RCTs) have generally shown that EGb 761® provides benefits in the symptomatic treatment of dementia (Table 4) [59,60,61,62,63]. The inclusion criteria for each meta-analysis differed; however, regardless of which RCTs were included, EGb 761® 120–240 mg/day was generally associated with improvements from baseline in cognition [59,60,61,62,63] and the ability to perform ADL [60, 62, 63], as well as improvements in global ratings [60, 63]. Of note, where reported, most of these meta-analyses had a high degree of heterogeneity, as shown by I2 scores of 81–100% and p < 0.00001 for heterogeneity for all analyses [60,61,62,63], with the exception of one ADL analysis with a moderately high I2 score of 62% [62]; therefore, the results should be interpreted with caution.
Compared with acetylcholinesterase inhibitors (AChEIs)
AChEIs, such as donepezil, galantamine and rivastigmine, are indicated for the symptomatic treatment of dementia in patients with mild-to-moderate dementia. Three RCTs have compared the efficacy of EGb 761® monotherapy [65, 67], EGb 761® + an AChEI [67, 68] and AChEI monotherapy [65, 67, 68].
The efficacy of EGb 761® 160 mg/day was not significantly different to that of donepezil 5 mg/day in the ITT population of a small (n = 76) 24-week RCT [65]. Cognition (as assessed by changes from baseline in SKT and CGI scores) significantly (p = 0.01) improved in the EGb 761® and donepezil groups relative to the placebo group. Cognition, as measured by Mini-Mental State Examination (MMSE) scores, improved in the EGb 761® and donepezil groups, and declined slightly in the placebo group, but the TDs were not statistically significant [65].
In 828 patients in the ICTUS (Impact of Cholinergic Treatment Use) study [68], the addition of EGb 761® (120 mg/day in 56% of patients) to treatment with an AChEIs (i.e. donepezil, galantamine, rivastigmine) provided some additional cognitive benefits relative to AChEI monotherapy. At 12 months, the TD for the change from baseline in MMSE scores favoured EGb 761® + an AChEI over AChEI monotherapy [1.86 ± standard error (SE) of 0.67; p = 0.006]. At 6 months, however, the TD for the change from baseline in MMSE scores (0.92 ± SE 0.55) did not reach statistical significance. There were also no statistically significant TDs with regard to the changes from baseline in ADAS-Cog and Instrumental-ADL scale scores at 6 and 12 months [68].
Likewise, in a small 22-week RCT in 96 patients with AD with NPS, changes from baseline in all outcome measures (SKT, NPI, GBS-ADL subscale, Hamilton Rating Scale for Depression, CDT and VFT) and response rates showed an apparent tendency to favour combination treatment with EGb 761® 240 mg/day + donepezil 5/10 mg/day over monotherapy with EGb 761® 240 mg/day or donepezil 5/10 mg/day [67]. However, the results did not differ to a statistically significant extent [67].
What is the tolerability profile of EGb 761®?
EGb 761® is generally well tolerated, according to the results of an in-depth analysis that combined toxicological data, long-term safety data from clinical studies and literature reports [70]. In addition, meta-analyses [60, 61, 63] of the tolerability of EGb 761® in RCTs, and the European Medicines Agency assessment report on Ginkgo biloba [71], did not find any safety issues. European SPCs for EGb 761® states that gastrointestinal upset, skin reactions and headache occur rarely during treatment [8, 9].
In response to reports of spontaneous bleeding in patients treated with Ginkgo biloba, two randomized, double-blind, placebo-controlled studies evaluated bleeding-related endpoints [72, 73]. In healthy volunteers, Ginkgo biloba extract (120, 240 and 480 mg/day for 14 days) did not cause any changes in platelet function or coagulation [72]. Similarly, in elderly patients with peripheral artery disease or at risk of cardiovascular disease, EGb 761® 300 mg/day coadministered with aspirin 325 mg/day for 4 weeks did not have any clinically or statistically significant effect on coagulation parameters [73].
What is the place of EGb 761® in the symptomatic treatment of mild-to-moderate dementia?
EGb 761® has positive effects on the symptoms of mild-to-moderate dementia, with changes from baseline in outcomes related to cognition, behaviour and global change that are generally better than those shown with placebo. The efficacy of EGb 761® in the treatment of mild-to-moderate dementia may be more marked in patients with NPS. The mechanisms of its neuroprotective effect are thought to be largely attributable to its antioxidant activity and ability to scavenge free radicals, and to its protective activity against Aβ-induced neurotoxicity and synthesis. The herbal extract is generally well tolerated, with no safety issues having been identified during many years of widespread use.
Limited data suggest that the efficacy of EGb 761® may be comparable to that with donepezil in patients with mild-to-moderate AD-related dementia, and that additional benefits may be gained by adding EGb 761® to existing treatment with an AChEI. Further studies on the efficacy of EGb 761® alone or in combination with an AChEI versus AChEI monotherapy, as well as long-term studies, would help confirm its place in the treatment of mild-to-moderate dementia.
Change history
23 November 2018
After publication in volume 34, issue 8, pages 358–366 [funder] requested that the article be Open Choice to make the article an open access publication
23 November 2018
After publication in volume 34, issue 8, pages 358?366 [funder] requested that the article be Open Choice to make the article an open access publication
References
Sanabria-Castro A, Alvarado-Echeverria I, Monge-Bonilla C. Molecular pathogenesis of Alzheimer’s disease: an update. Ann Neurosci. 2017;24(1):46–54.
Kar S, Slowikowski S, Westaway D, et al. Interactions between β-amyloid and central cholinergic neurons: implications for Alzheimer’s disease. J Psychiatry Neurosci. 2004;29(6):427–41.
O’Brien JT, Holmes C, Jones M, et al. Clinical practice with anti-dementia drugs: a revised (third) consensus statement from the British Association for Psychopharmacology. J Psychopharmacol. 2017;31(2):147–68.
Wasik A, Antkiewicz-Michaluk L. The mechanism of neuroprotective action of natural compounds. Pharmacol Rep. 2017;69(5):851–60.
Maclennan KM, Darlington CL, Smith PF. The CNS effects of Ginkgo biloba extracts and ginkgolide B. Prog Neurobiol. 2002;67(3):235–57.
Kressmann S, Muller WE, Blume HH. Pharmaceutical quality of different Ginkgo biloba brands. J Pharm Pharmacol. 2002;54(5):661–9.
Kressmann S, Biber A, Wonnemann M, et al. Influence of pharmaceutical quality on the bioavailability of active components from Ginkgo biloba preparations. J Pharm Pharmacol. 2002;54(11):1507–14.
Tanakan [standardized ginkgo biloba extract (EGb 761)] 40 mg film-coated tablets and 40 mg/ml oral solution: summary of product characteristics (Czech Republic). Boulogne-Billancourt: Ipsen Pharma; 2016.
Tanakan [standardized ginkgo biloba extract (EGb 761)] 40 mg film-coated tablets and 40 mg/ml oral solution: summary of product characteristics (Lithuania). Boulogne-Billancourt: Ipsen Pharma; 2015.
DeFeudis FV, Drieu K. Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. Curr Drug Targets. 2000;1(1):25–58.
Ahlemeyer B, Krieglstein J. Neuroprotective effects of Ginkgo biloba extract. Cell Mol Life Sci. 2003;60(9):1779–92.
De Feudis F. Bilobalide and neuroprotection. Pharmacol Res. 2002;46(6):565–8.
Beck SM, Ruge H, Schindler C, et al. Effects of Ginkgo biloba extract EGb 761® on cognitive control functions, mental activity of the prefrontal cortex and stress reactivity in elderly adults with subjective memory impairment: a randomized double-blind placebo-controlled trial. Hum Psychopharmacol. 2016;31(3):227–42.
Bastianetto S, Quirion R. EGb 761 is a neuroprotective agent against beta-amyloid toxicity. Cell Mol Biol (Noisy-le-Grand). 2002;48(6):693–7.
Chen JX, Yan SS. Role of mitochondrial amyloid-beta in Alzheimer’s disease. J Alzheimers Dis. 2010;20(Suppl 2):S569–78.
Colciaghi F, Borroni B, Zimmermann M, et al. Amyloid precursor protein metabolism is regulated toward alpha-secretase pathway by Ginkgo biloba extracts. Neurobiol Dis. 2004;16(2):454–60.
Ude C, Schubert-Zsilavecz M, Wurglics M. Ginkgo biloba extracts: a review of the pharmacokinetics of the active ingredients. Clin Pharmacokinet. 2013;52(9):727–49.
Bridi R, Crossetti FP, Steffen VM, et al. The antioxidant activity of standardized extract of Ginkgo biloba (EGb 761) in rats. Phytother Res. 2001;15(5):449–51.
Wei T, Ni Y, Hou J, et al. Hydrogen peroxide-induced oxidative damage and apoptosis in cerebellar granule cells: protection by Ginkgo biloba extract. Pharmacol Res. 2000;41(4):427–33.
Sastre J, Millan A, Garcia de la Asuncion J, et al. A Ginkgo biloba extract (EGb 761) prevents mitochondrial aging by protecting against oxidative stress. Free Radic Biol Med. 1998;24(2):298–304.
Rocher MN, Carre D, Spinnewyn B, et al. Long-term treatment with standardized Ginkgo biloba extract (EGb 761) attenuates cognitive deficits and hippocampal neuron loss in a gerbil model of vascular dementia. Fitoterapia. 2011;82(7):1075–80.
Wang Y, Wang L, Wu J, et al. The in vivo synaptic plasticity mechanism of EGb 761-induced enhancement of spatial learning and memory in aged rats. Br J Pharmacol. 2006;148(2):147–53.
Williams B, Watanabe CMH, Schultz PG, et al. Age-related effects of Ginkgo biloba extract on synaptic plasticity and excitability. Neurobiol Aging. 2004;25(7):955–62.
Tchantchou F, Xu Y, Wu Y, et al. EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer’s disease. FASEB J. 2007;21(10):2400–8.
Chandrasekaran K, Mehrabian Z, Spinnewyn B, et al. Neuroprotective effects of bilobalide, a component of Ginkgo biloba extract (EGb 761) in global brain ischemia and in excitotoxicity-induced neuronal death. Pharmacopsychiatry. 2003;36(Suppl 1):S89–94.
Mdzinarishvili A, Sumbria R, Lang D, et al. Ginkgo extract EGb761 confers neuroprotection by reduction of glutamate release in ischemic brain. J Pharm Pharm Sci. 2012;15(1):94–102.
Soulie C, Nicole A, Christen Y, et al. The Ginkgo biloba extract EGb 761 increases viability of hnt human neurons in culture and affects the expression of genes implicated in the stress response. Cell Mol Biol. 2002;48(6):641–6.
Mohamed NE, Abd El-Moneim AE. Ginkgo biloba extract alleviates oxidative stress and some neurotransmitters changes induced by aluminum chloride in rats. Nutrition. 2017;35:93–9.
Shi C, Zhao L, Zhu B, et al. Protective effects of Ginkgo biloba extract (EGb761) and its constituents quercetin and ginkgolide B against beta-amyloid peptide-induced toxicity in SH-SY5Y cells. Chem Biol Interact. 2009;181(1):115–23.
Smith JV, Luo Y. Elevation of oxidative free radicals in Alzheimer’s disease models can be attenuated by Ginkgo biloba extract EGb 761. J Alzheimers Dis. 2003;5(4):287–300.
Wang N, Chen X, Geng D, et al. Ginkgo biloba leaf extract improves the cognitive abilities of rats with d-galactose induced dementia. J Biomed Res. 2013;27(1):29–36.
Yao Z, Drieu K, Papadopoulos V. The Ginkgo biloba extract EGb 761 rescues the PC12 neuronal cells from beta-amyloid-induced cell death by inhibiting the formation of beta-amyloid-derived diffusible neurotoxic ligands. Brain Res. 2001;889(1–2):181–90.
Luo Y, Smith JV, Paramasivam V, et al. Inhibition of amyloid-beta aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761. Proc Natl Acad Sci USA. 2002;99(19):12197–202.
Stackman RW, Eckenstein F, Frei B, et al. Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimer’s disease by chronic Ginkgo biloba treatment. Exp Neurol. 2003;184(1):510–20.
Yao Z, Han Z, Drieu K, et al. Ginkgo biloba extract (Egb 761) inhibits β-amyloid production by lowering free cholesterol levels. J Nutr Biochem. 2004;15(12):749–56.
Longpré F, Garneau P, Christen Y, et al. Protection by EGb 761 against β-amyloid-induced neurotoxicity: involvement of NF-κB, SIRT1, and MAPKs pathways and inhibition of amyloid fibril formation. Free Radic Biol Med. 2006;41(12):1781–94.
Rhein V, Giese M, Baysang G, et al. Ginkgo biloba extract ameliorates oxidative phosphorylation performance and rescues Aβ-induced failure. PLoS One. 2010;5(8):e12359.
Kwon KJ, Lee EJ, Cho KS, et al. Ginkgo biloba extract (Egb761) attenuates zinc-induced tau phosphorylation at Ser262 by regulating GSK3beta activity in rat primary cortical neurons. Food Funct. 2015;6(6):2058–67.
Paganelli RA, Benetoli A, Milani H. Sustained neuroprotection and facilitation of behavioral recovery by the Ginkgo biloba extract, EGb 761, after transient forebrain ischemia in rats. Behav Brain Res. 2006;174(1):70–7.
Zhao J, Jin KK, Wu L, et al. Effects of extract of Ginkgo biloba on learning and memory ability and NGF and NT-3 expression in diabetic rats. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2012;28(5):467–71.
Winter JC. The effects of an extract of Ginkgo biloba, EGb 761, on cognitive behavior and longevity in the rat. Physiol Behav. 1998;63(3):425–33.
Shif O, Gillette K, Damkaoutis CM, et al. Effects of Ginkgo biloba administered after spatial learning on water maze and radial arm maze performance in young adult rats. Pharmacol Biochem Behav. 2006;84(1):17–25.
Chen LE, Wu F, Zhao A, et al. Protection efficacy of the extract of Ginkgo biloba against the learning and memory damage of rats under repeated high sustained +Gz exposure. Evid Based Complement Altern Med. 2016;2016:6320586.
Tighilet B, Lacour M. Pharmacological activity of the Ginkgo biloba extract (EGb 761) on equilibrium function recovery in the unilateral vestibular neurectomized cat. J Vestib Res. 1995;5(3):187–200.
Silberstein RB, Pipingas A, Song J, et al. Examining brain-cognition effects of Ginkgo biloba extract: brain activation in the left temporal and left prefrontal cortex in an object working memory task. Evid Based Complement Altern Med. 2011;2011:164139.
Schneider LS, DeKosky ST, Farlow MR, et al. A randomized, double-blind, placebo-controlled trial of two doses of Ginkgo biloba extract in dementia of the Alzheimer’s type. Curr Alzheimer Res. 2005;2(5):541–51.
Kanowski S, Hoerr R. Ginkgo biloba extract EGb 761 in dementia: intent-to-treat analyses of a 24-week, multi-center, double-blind, placebo-controlled, randomized trial. Pharmacopsychiatry. 2003;36(6):297–303.
Le Bars PL, Katz MM, Berman N, et al. A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA. 1997;278(16):1327–32.
Le Bars PL, Kieser M, Itil KZ. A 26-week analysis of a double-blind, placebo-controlled trial of the Ginkgo biloba extract EGb 761 in dementia. Dement Geriatr Cogn Disord. 2000;11:230–7.
McCarney R, Fisher P, Iliffe S, et al. Ginkgo biloba for mild to moderate dementia in a community setting: a pragmatic randomised, parallel-group, double-blind, placebo-controlled trial. Int J Geriatr Psychiatry. 2008;23(12):1222–30.
van Dongen M, van Rossum E, Kessels A, et al. Ginkgo for elderly people with dementia and age-associated memory impairment: a randomized clinical trial. J Clin Epidemiol. 2003;56(4):367–76.
van Dongen MCJM, van Rossum E, Kessels AGH, et al. The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: new results of a randomized clinical trial. J Am Geriatr Soc. 2000;48(10):1183–94.
Herrschaft H, Nacu A, Likhachev S, et al. Ginkgo biloba extract EGb 761® in dementia with neuropsychiatric features: a randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg. J Psychiatr Res. 2012;46(6):716–23.
Ihl R, Bachinskaya N, Korczyn AD, et al. Efficacy and safety of a once-daily formulation of Ginkgo biloba extract EGb 761 in dementia with neuropsychiatric features: a randomized controlled trial. Int J Geriatr Psychiatry. 2011;26(11):1186–94.
Ihl R, Tribanek M, Bachinskaya N. Efficacy and tolerability of a once daily formulation of Ginkgo biloba extract EGb 761® in Alzheimer’s disease and vascular dementia: results from a randomised controlled trial. Pharmacopsychiatry. 2012;45(2):41–6.
Napryeyenko O, Borzenko I. Ginkgo biloba special extract in dementia with neuropsychiatric features: a randomised, placebo-controlled, double-blind clinical trial. Arzneimittelforschung. 2007;57(1):4–11.
Napryeyenko O, Sonnik G, Tartakovsky I. Efficacy and tolerability of Ginkgo biloba extract EGb 761 by type of dementia: analyses of a randomised controlled trial. J Neurol Sci. 2009;283(1–2):224–9.
Nikolova G, Yancheva S, Raychev I, et al. Ginkgo biloba extract in dementia: a 22-week randomised, placebo-controlled, double-blind trial [in Bulgarian]. Bulg Neurol. 2013;14(3):139–43.
Brondino N, De Silverstri A, Re S, et al. A systematic review and meta-analysis of Ginkgo biloba in neuropsychiatric disorders: from ancient tradition to modern-day medicine. Evid Based Complement Altern Med. 2013;2013:915691. https://doi.org/10.1155/2013/915691.
Gauthier S, Schlaefke S. Efficacy and tolerability of Ginkgo biloba extract EGb 761® in dementia: a systematic review and meta-analysis of randomized placebo-controlled trials. Clin Interv Aging. 2014;9:2065–77.
Hashiguchi M, Ohta Y, Shimizu M, et al. Meta-analysis of the efficacy and safety of Ginkgo biloba extract for the treatment of dementia. J Pharm Health Care Sci. 2015;1:14. https://doi.org/10.1186/s40780-015-0014-7.
Jiang L, Su L, Cui H, et al. Ginkgo biloba extract for dementia: a systematic review. Shanghai Arch Psychiatry. 2013;25(1):10–2.
Tan MS, Yu JT, Tan CC, et al. Efficacy and adverse effects of Ginkgo biloba for cognitive impairment and dementia: a systematic review and meta-analysis. J Alzheimers Dis. 2015;43(2):589–603.
Maurer K, Ihl R, Dierks T, et al. Clinical efficacy of Ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type. J Psychiatr Res. 1997;31(6):645–55.
Mazza M, Capuano A, Bria P, et al. Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer’s dementia in a randomized placebo-controlled double-blind study. Eur J Neurol. 2006;13(9):981–5.
Gaus W, et al. An example for an underpowered study: a comment on Ginkgo biloba for mild to moderate dementia in a community setting by McCarney et al. [letter]. Int J Geriatr Psychiatry. 2009;24(2):216–7.
Yancheva S, Ihl R, Nikolova G, et al. Ginkgo biloba extract EGb 761®, donepezil or both combined in the treatment of Alzheimer’s disease with neuropsychiatric features: a randomised, double-blind, exploratory trial. Aging Ment Health. 2009;13(2):183–90.
Canevelli M, Adali N, Kelaiditi E, et al. Effects of Gingko biloba supplementation in Alzheimer’s disease patients receiving cholinesterase inhibitors: data from the ICTUS study. Phytomedicine. 2014;21(6):888–92.
Kanowski S, Herrmann WM, Stephan K, et al. Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Pharmacopsychiatry. 1996;29(2):47–56.
Heinonen T, Gaus W. Cross matching observations on toxicological and clinical data for the assessment of tolerability and safety of Ginkgo biloba leaf extract. Toxicology. 2015;327:95–115.
European Union herbal monograph on Ginkgo biloba L., folium. London; European Medicines Agency; 2015.
Dit Sollier CB, Caplain H, Drouet L. No alteration in platelet function or coagulation induced by EGb761 in a controlled study. Clin Lab Haematol. 2003;25(4):251–3.
Gardner C, Zehnder J, Rigby A, et al. Effects of Ginkgo biloba (EGb 761) and aspirin on platelet aggregation and platelet function analysis among older adults at risk of cardiovascular disease: a randomized clinical trial. Blood Coagul Fibrinolysis. 2007;18(8):787–93.
Acknowledgements
The manuscript was reviewed by: M. Mazza, Department of Neurosciences, Institute of Psychiatry, Catholic University of Sacred Heart, Rome, Italy; M.C. Woodward, Aged and Residential Care Services, Austin Health, University of Melbourne, Heidelberg, VIC, Australia; W.S. Zirker, Division of Geriatric Medicine, Crozer-Chester Medical Center, Upland, PA, USA. During the peer review process, Ipsen Pharma, the marketing-authorization holder of EGb 761®, was also offered an opportunity to provide a scientific accuracy review of their data. Changes resulting from comments received were made on the basis of scientific and editorial merit.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
The preparation of this review was not supported by any external funding.
Conflict of interest
K. McKeage and K.A. Lyseng-Williamson are employees of Adis/Springer, are responsible for the article content and declare no conflicts of interest.
Additional information
The original version of this article was revised due to a retrospective Open Access request.
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.
About this article
Cite this article
McKeage, K., Lyseng-Williamson, K.A. Ginkgo biloba extract EGb 761® in the symptomatic treatment of mild-to-moderate dementia: a profile of its use. Drugs Ther Perspect 34, 358–366 (2018). https://doi.org/10.1007/s40267-018-0537-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40267-018-0537-8