The dried leaf of the ginkgo tree has been used medicinally for thousands of years. Multiple pharmacologically active compounds have been isolated from ginkgo. Flavonoids have antioxidant and free radical scavenging ability, and terpene lactones have platelet-activating factor antagonist activity. In addition, ginkgo extracts increase the production of nitric oxide and activate certain central neurotransmitters, including the cholinergic system, which may contribute to their beneficial effects on memory and cognition. EGb761, the formulation that has been studied most extensively, is standardized to contain 24% flavonoid glycosides and 6% terpene lactones.
In general, ginkgo is well tolerated in healthy adults at recommended doses for up to 6 months. Allergic skin reactions, gastrointestinal disturbances, and headaches occur in less than 2% of patients. There are theoretical concerns about a risk of increased bleeding because antiplatelet activating factor activity has been demonstrated in vitro. Cases of increased bleeding in patients taking ginkgo have been reported, but establishing a causal relationship is challenging because many of these patients had other risk factors including age and medications such as aspirin, NSAIDs, or warfarin. Of note, no excess bleeding complications have been reported in clinical trials, and differences in coagulation, platelet function, or pharmacokinetics have not been reported in healthy volunteers taking warfarin or in men taking ticlopidine. Ginkgo should still be used cautiously in patients with bleeding disorders or who are taking aspirin, NSAIDs, warfarin or other anticoagulants, or other botanicals that may increase the risk of bleeding.
More than 400 studies over the past 30 years have investigated ginkgo’s ability to improve blood flow in a variety of conditions, including memory impairment, dementia, peripheral vascular disease, Raynaud phenomenon, migraine headache, and acute mountain sickness. A standardized form of ginkgo leaf extract (EGb761) is approved by the German Commission E for the treatment of cognitive impairment and intermittent claudication.
Over the past several decades, there have been conflicting data regarding the effect of Gingko biloba on cognition. Early studies that assessed ginkgo’s efficacy on cognitive function in the elderly showed a modest improvement when compared with placebo. The longest of these studies (1 year) showed stabilization of cognitive and functional abilities in 309 demented patients treated with EGb761 compared with placebo, with no differences in adverse outcomes. A double-blind randomized controlled trial of 118 elders over 85 years of age (when medication adherence was taken into account), a larger (n = 400) 2007 double-blind randomized controlled trial, and a small (n = 60) double-blind randomized controlled trial all concluded that low-dose G biloba produced effects equal to low-dose donepezil in patients aged 50–80 years with mild or moderate dementia. A 2009 review found consistent evidence of benefit for specific cognitive functions (eg, long-term verbal and nonverbal memory, selective attention, and some executive processes). In 2010, two meta-analyses were published. A bivariate meta-analysis of six qualifying studies that claimed to fully account for the baseline cognitive changes that would be expected in cohorts of Alzheimer dementia patients concluded that there was a significant benefit of G biloba on their symptoms. In 2012, two of three additional large randomized controlled trials showed benefit from ginkgo on cognitive and neuropsychiatric symptoms. Similarly, a meta-analysis of nine trials looking at several types of dementia found significant benefit of G biloba for Alzheimer dementia. A 2014 randomized, controlled trial involving 160 patients with mild cognitive impairment who were treated with EGb721 120 mg twice a day orally found a reduction in neuropsychiatric symptoms compared to placebo at 24 weeks. A 2015 meta-analysis reviewed nine trials of 22–26 weeks’ duration and concluded that the ginkgo leaf extract EGb-761 dosed at 240 mg orally daily was able to stabilize or slow decline in patients with dementia and cognitive impairment, particularly those with neuropsychiatric symptoms.
On the other hand, a 2007 systematic review concluded that ginkgo did not have predictable and clinically significant benefits in patients with dementia. A 2009 Cochrane review concluded that use of G biloba appears safe, but the evidence that it has clinically significant benefit for people with dementia or cognitive impairment was inconsistent. A well-designed, large, National Institutes of Health–funded study published in 2012 showed that ginkgo (EGb721 120 mg twice a day orally) did not prevent or impede further cognitive decline in dementia in more than 3000 elderly persons with normal or mildly impaired cognitive function who were monitored for a mean of 6 years.
A 2013 20-year follow-up study of over 3600 nondemented elders using the EGb721 extract found that Mini Mental Status Examination scores declined significantly less rapidly in those taking ginkgo versus placebo or piracetam (a nootropic drug used outside of the United States for cognitive impairment). A 2016 analysis of systemic reviews of G biloba concluded that there is clear evidence supporting the use of G biloba extract for both dementia and mild cognitive impairment. A 2017 systematic review came to the more cautious conclusion that G biloba is potentially beneficial for the improvement of cognitive function and safe for use in patients with mild cognitive impairment or Alzheimer disease but that more research is warranted due to methodologic quality of some trials. This was supported by another 2018 meta-analysis of randomized controlled trials studying EGb761 in the treatment of dementia; this study found that 22- to 24-week treatment with a standardized 240 mg EGb761 dose may lead to improvements in behavioral and psychological symptoms of dementia, as also further supported by significant decreases in caregiver distress.
In summary, there are conflicting data on the effect of G biloba on cognition; however, with the paucity of options in the treatment of mild cognitive decline, ginkgo may be considered an option.
A meta-analysis of six trials examining the use of G biloba as adjunctive therapy for chronic schizophrenia concluded that ginkgo significantly improves both total and negative symptoms of chronic schizophrenia. Also relevant to this patient group is a randomized, double-blind, placebo-controlled trial of 157 people that showed a significant reduction in tardive dyskinesia symptoms. Furthermore, a 2016 systemic review and meta-analysis of eight randomized controlled trials from China including 1033 patients concluded that gingko provided significant benefit as an adjuvant to conventional pharmaceutical therapy in ameliorating both the total and negative symptoms of schizophrenia.
Ginkgo has also been evaluated for its effect on intermittent claudication. A meta-analysis of nine randomized, placebo-controlled, double-blind trials of patients treated with EGb761 showed a modest treatment effect in the increase of pain-free walking distance in favor of ginkgo over placebo. A 2013 Cochrane review of 14 randomized controlled trials concluded that the walking distance benefit given by ginkgo (64.5 meters on treadmill) was of questionable clinical significance. Importantly, a secondary analysis of the large Ginkgo Evaluation of Memory (GEM) Study found significantly fewer events related to peripheral vascular disease (ie, vascular surgery or amputation) in the ginkgo arm.
There is insufficient research to make conclusions regarding the efficacy of ginkgo in treating acute altitude sickness, tinnitus, Raynaud phenomenon, or migraine headache. Two studies with a total of 119 patients showed benefit of ginkgo on age-related macular degeneration; however, a Cochrane review concludes further research is needed.
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