Clinical use of ginkgo biloba

INTRODUCTION — Ginkgo biloba, more commonly known as ginkgo, has been used medicinally for over 1000 years [1]. The ginkgo tree is the world's oldest living tree species (picture 1).

Ginkgo represents one of the most studied and commonly used herbal remedies in the world. The National Health Interview Survey found that ginkgo was the ninth most popular natural product in the United States in 2012 [2]. Over 400 clinical trials have been performed looking at a variety of medicinal properties and clinical uses. Ginkgo leaf extract has been used for its antioxidant properties; for a number of vascular problems; and for the treatment of memory loss, dementia, and macular degeneration [3]. However, randomized trials evaluating the use of ginkgo biloba for the treatment and prevention of many diseases and conditions have failed to demonstrate consistent benefit.

PROPOSED MECHANISMS OF ACTION — It is thought that there are two main groups of active constituents responsible for ginkgo biloba's purported medicinal effects: terpene lactones and ginkgo flavone glycosides. These are present in varying concentrations in the leaf of the ginkgo tree [1]. Approximately 40 different flavonoids have been isolated, including ginkgetin, bilobetin, and sciadopitysin [4]. Terpenes isolated include a number of ginkgolides and diterpenes, most importantly the ginkgolides A, B, and C, along with bilobalide [5].

The bioactive properties of ginkgo biloba extracts are varied. In animal studies, ginkgo biloba extract appears to decrease glucose utilization in brain areas mediating somatosensory processing and vigilance, inhibit stress-induced corticosteroid release [6], and protect against age-related changes in the mouse hippocampus [7]. In other animal studies, ginkgo biloba extracts have been demonstrated to inhibit nitric oxide [8,9], induce vasodilation [10], and reversibly inhibit brain monoamine oxidase A and B [11], and they may act as scavengers for free radicals [12], which are possible mediators of the lipid peroxidation and cell damage observed in Alzheimer disease [13].

In in vitro studies, the terpene lactones inhibit the binding of platelet-activating factor (PAF) to its membrane receptor [14]. In addition, ginkgo biloba demonstrates antioxidant properties [15] and inhibits acetylcholinesterase [16].

PROPOSED INDICATIONS AND CLINICAL TRIALS — The majority of studies for the clinical use of ginkgo biloba are for the treatment and prevention of memory issues, cognitive impairment, or dementia.

Dementia, cognitive impairment, memory enhancement

Treatment — Data on the efficacy of ginkgo biloba extract for the treatment of Alzheimer or vascular dementia are mixed [17-22]. (See "Treatment of Alzheimer disease".)

Although a small 1997 trial including adults with dementia (Alzheimer disease and vascular dementia) suggested that ginkgo biloba could prevent short-term cognitive deterioration [21], in subsequent, higher-quality trials, results were inconsistent in terms of beneficial effects on cognition, function, mood, and caregiver stress. In a systematic review including trials of ginkgo for cognitive impairment and dementia, three of the four trials did not find a benefit of ginkgo over placebo [23]. Adverse events for ginkgo and placebo were similar.

Prevention — Ginkgo biloba appears to be ineffective in preventing progression to dementia, both in older adults with normal cognition and in those with mild cognitive impairment (MCI) [24-26]. In addition, ginkgo does not enhance memory in cognitively normal adults [27,28]. As examples:

●The Ginkgo Evaluation of Memory (GEM) study was a large, multicenter trial that randomly assigned over 3000 adults ages 75 and older (approximately 15 percent with MCI at baseline) to ginkgo biloba extract 120 mg twice daily or placebo [29]. Ginkgo biloba did not reduce the risk of dementia in cognitively normal adults or in those with MCI at six years.

●In a small trial including 230 cognitively intact adults over age 60 years, ginkgo biloba extract did not show a beneficial effect for memory enhancement [27]. Among participants receiving ginkgo biloba 40 mg three times daily for six weeks, there was no improvement in memory (as measured by standard neuropsychological tests, self-reported memory function, or global rating by spouses, friends, and relatives) compared with placebo. The ginkgo content of the preparation was not verified.

●In another small trial including 214 patients with memory impairment from a variety of causes, participants received extract of ginkgo biloba (EGb) 761 (at a high dose of 240 mg or a low dose of 160 mg) or placebo for 24 weeks [26]. There was no improvement in memory function with ginkgo compared with placebo.

Other studies have found contradictory results [18,30-34]. However, most of these studies were small, and the beneficial effects did not cover a broad range of findings nor were they consistent. In one randomized trial including 118 people over age 84, there was a nonstatistically significant trend toward less cognitive decline with ginkgo, but also an increased incidence of strokes [35].

Other disorders — Ginkgo biloba has been evaluated in the treatment of other disorders, but the trials are small and high-quality evidence of efficacy for the treatment of most conditions is lacking.

Psychiatric disorders — Ginkgo biloba has been studied as a treatment for depression:

●One small study including 40 older adult patients with depression compared treatment with ginkgo biloba extract with placebo [36]. The average total score on the Hamilton Depression Scale after four weeks fell significantly in those treated with ginkgo biloba extract compared with placebo.

●In a small double-blind trial including 27 patients, ginkgo was not effective in preventing seasonal affective disorder [37].

Movement disorders — Ginkgo biloba may be helpful in reducing antipsychotic-induced tardive dyskinesia, although high-quality data are limited. This is reviewed elsewhere. (See "Tardive dyskinesia: Prevention, treatment, and prognosis", section on 'Other drug treatments'.)

Antidepressant-associated sexual dysfunction — In an open-label trial (in which study participants and researchers are unblinded as to which treatment individuals receive) including 63 adults with selective serotonin reuptake inhibitor (SSRI)-associated sexual dysfunction, 84 percent of patients reported improvement after four weeks of treatment with ginkgo biloba extract [38]. However, in two small randomized trials including patients with SSRI-associated sexual dysfunction, treatment with ginkgo failed to show benefits compared with placebo [39,40].

Vertigo — In one small trial including 70 patients with recent-onset vertigo of undetermined etiology, the use of ginkgo biloba extract reduced vertigo symptoms compared with placebo (47 versus 18 percent, respectively) [41].

Vitiligo — There is limited evidence that ginkgo may be effective in the management of vitiligo [42,43]; this is reviewed elsewhere. (See "Vitiligo: Management and prognosis", section on 'Dietary supplements'.)

Ophthalmic conditions — A 2013 systematic review identified two small six-month trials for macular degeneration, one comparing ginkgo biloba extract with placebo (n = 20) and the other comparing two different doses of the extract (n = 99); the results were not pooled [44]. Although there was some suggestion of benefit in these trials, larger and longer trials are necessary to assess ginkgo's efficacy in the treatment of macular degeneration.

In a small trial, ginkgo biloba extract improved visual field test results in some patients with normal-tension glaucoma [45].

Peripheral vascular disease — There is evidence that ginkgo is not effective for claudication in patients with peripheral vascular disease [46-48]. (See "Management of claudication due to peripheral artery disease", section on 'Ineffective'.)

Altitude sickness — Most studies have found that ginkgo biloba does not prevent altitude sickness symptoms [49-52]. In a network meta-analysis, ginkgo alone or as an adjunct to acetazolamide was not beneficial in preventing acute mountain sickness [52]. However, in an earlier small trial not included in the meta-analysis involving 44 Himalayan mountain climbers, those treated with ginkgo biloba extract developed fewer mountain sickness symptoms than climbers taking placebo [49].

Tinnitus — Despite the common use of ginkgo for the treatment of tinnitus, well-designed studies do not support efficacy for this disorder. A systematic review of 12 trials found a high risk of bias due to inadequate reporting of blinding, treatment allocation, outcome heterogeneity, and selection bias. No meaningful conclusions could be made regarding the efficacy and safety of ginkgo for tinnitus [53]. The treatment of tinnitus is discussed separately. (See "Treatment of tinnitus".)

SAFETY — Ginkgo biloba extract generally appears to be safe and well-tolerated when used in standard doses (see 'Dose' below) in clinical trials lasting up to one year [1].

Adverse effects

●Bleeding risk – There are several case reports of bleeding associated with ginkgo extracts [54]:

•Combined use of high-dose aspirin (325 mg daily) and ginkgo resulted in spontaneous bleeding into the anterior chamber of the eye [55]

•Spontaneous bilateral subdural hematoma with a prolonged bleeding time [56]

•Chronic left frontal subdural hematoma [57]

•Subarachnoid hemorrhage [58,59]

•Bilateral hematoma after rhytidoplasty and blepharoplasty [60]

•Gastrointestinal bleeding and epistaxis associated with concomitant use of selective serotonin reuptake inhibitors (SSRIs) [61]

However, in a meta-analysis including 18 randomized trials and almost 2000 patients, there was no significant effect of ginkgo biloba on platelet aggregation, prothrombin time, or activated partial thromboplastin time [62].

●Other – Mild adverse effects include gastrointestinal upset and headaches [1,63]. In addition, ingestion of ginkgo's non-leaf parts (eg, seed, fruit, or nut) can result in allergic reactions including blisters, erythema, and itching [64-66].

Contraindications

●Caution should be exercised with ginkgo in patients with bleeding disorders or those who take anticoagulant drugs. The risk of spontaneous bleeding may be increased when ginkgo biloba extract is combined with nonsteroidal antiinflammatory drugs (NSAIDs) and anticoagulants such as heparin or warfarin [1]. Analysis of a large database using natural language processing identified 11,003 patients who used ginkgo and warfarin concurrently. Compared with users of warfarin only, the ginkgo and warfarin group had an increased risk of an adverse bleeding event (hazard ratio 1.38, 95% CI 1.20-1.58) [67]. Concomitant use of ginkgo with these agents should be avoided.

Episodes of serious bleeding from the use of ginkgo and low-dose (81 mg daily) aspirin prophylaxis have not been reported; although this combination is likely safe, caution should be exercised.

In addition, caution should be used when ginkgo is combined with other herbs believed to increase bleeding (eg, garlic, ginseng, ginger).

Few data exist about the risk of perioperative complications due to ginkgo use. Based on a literature review, some experts recommended that, because of the potential bleeding risk associated with ginkgo, it should be discontinued at least three days prior to a planned surgical procedure [68].

●There is a lack of data regarding use in pregnancy and lactation; due to absent safety information, ginkgo should not be used in this population [1].

●There are case reports of seizure associated with ginkgo use [69-71]. Whether ginkgo lowers seizure threshold is uncertain, however, ginkgo should be used with caution in patients with seizure disorders.

Potential interactions

●The major components of ginkgo biloba preparations (terpenes, flavonol glycosides) do not significantly inhibit human cytochrome P450 isoforms in vitro [72]. However, other components of ginkgo (flavonol aglycones, the bioflavonoid amentoflavone) do inhibit CYP1A2 and CYP3A4. The clinical importance of these potential interactions is uncertain.

●Ginkgo biloba extract in high doses may theoretically potentiate the effects of monoamine oxidase inhibitors (MAOIs) due to the inhibition of the uptake of serotonin and dopamine [73]. One study showed reversible inhibition of monoamine oxidase in rats fed ginkgo extract [74]. This has led some to caution against the use of ginkgo biloba extract in patients taking other antidepressants due to the potential risk of precipitating serotonin syndrome (agitation, hyperthermia, diaphoresis, tachycardia, and neuromuscular disturbances including rigidity) (see "Serotonin syndrome (serotonin toxicity)", section on 'Pharmacology and cellular toxicology' and "Drug fever", section on 'Serotonin syndrome'). There are no reports of serotonin syndrome in studies of ginkgo for SSRI-induced sexual dysfunction. However, patients should be advised of the potential for these interactions, although the true risk is unknown [75].

●Ginkgo 90 mg daily did not show any adverse effects on the pharmacokinetics of donepezil 5 mg daily when administered together [76]. Potential adverse or synergistic interactions with other medications used in treating dementia are unknown.

ADMINISTRATION

Dose — The majority of the studies evaluating ginkgo extract utilized the standardized extract of ginkgo biloba (EGb) 761. EGb 761 is standardized to contain 24% flavonoid glycosides and 6% terpenoids [77]. Typical dosages of EGb 761 used in studies and recommended by manufacturers are 40 mg three times daily or 80 mg twice daily.

Standardization of available products — Quality control of herbal and dietary supplements, including ginkgo biloba, is variable. Despite attempts by the US Food and Drug Administration to improve regulation of quality and safety standards for dietary supplements [78], experts have criticized current standards as insufficient and enforcement activities as inadequate [79,80]. (See "Overview of herbal medicine and dietary supplements", section on 'Regulation in the United States' and "Overview of herbal medicine and dietary supplements", section on 'International regulation'.)

If patients choose to use ginkgo, they should be advised to use brands which have passed specified quality criteria by independent commercial laboratories such as ConsumerLab.com or USP-verified dietary supplements.

SUMMARY AND RECOMMENDATIONS

●Ginkgo biloba, more commonly known as ginkgo, has been used medicinally for over 1000 years. Patients commonly use ginkgo for a wide range of conditions. (See 'Introduction' above.)

●Randomized trials evaluating the use of ginkgo biloba for the treatment and prevention of many diseases and conditions have failed to demonstrate consistent benefit. (See 'Proposed indications and clinical trials' above.)

●Ginkgo is generally well tolerated, although case reports of bleeding complications suggest that it should not be used perioperatively or in patients with known bleeding disorders. In addition, ginkgo should be avoided or used with caution in patients receiving anticoagulants. (See 'Safety' above.)

●Quality control of herbal and dietary supplements, including ginkgo biloba, is variable. If patients choose to use ginkgo, they should be advised to use brands that have passed specified quality criteria by independent commercial laboratories. (See 'Standardization of available products' above.)