Abstract

Background

Tinnitus is a symptom defined as the perception of sound in the absence of an external source. In England alone there are an estimated ¾ million general practice consultations every year where the primary complaint is tinnitus, equating to a major burden on healthcare services. Clinical management strategies include education and advice, relaxation therapy, tinnitus retraining therapy (TRT), cognitive behavioural therapy (CBT), sound enrichment using ear‐level sound generators or hearing aids, and drug therapies to manage co‐morbid symptoms such as insomnia, anxiety or depression. 

Objectives

To assess the effects of Ginkgo biloba for tinnitus in adults and children.

Search methods

The Cochrane ENT Information Specialist searched the Cochrane ENT Register; CENTRAL (2022, Issue 6); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 7 June 2022.

Selection criteria

Randomised controlled trials (RCTs) recruiting adults and children with acute or chronic subjective tinnitus. We included studies where the intervention involved Ginkgo biloba and this was compared to placebo, no intervention, or education and information. Concurrent use of other medication or other treatment was acceptable if used equally in each group. Where an additional intervention was used equally in both groups, we analysed this as a separate comparison. The review included all courses of Ginkgo biloba, regardless of dose regimens or formulations, and for any duration of treatment.

Data collection and analysis

We used standard Cochrane methods. Our primary outcomes were tinnitus symptom severity measured as a global score on a multi‐item tinnitus questionnaire and serious adverse effects (bleeding, seizures). Our secondary outcomes were tinnitus loudness (change in subjective perception), tinnitus intrusiveness, generalised depression, generalised anxiety, health‐related quality of life and other adverse effects (gastrointestinal upset, headache, allergic reaction). We used GRADE to assess the certainty of the evidence for each outcome.

Main results

This review included 12 studies (with a total of  1915 participants). Eleven studies compared the effects of Ginkgo biloba with placebo and one study compared the effects of Ginkgo biloba with hearing aids to hearing aids alone. All included studies were parallel‐group RCTs. In general, risk of bias was high or unclear due to selection bias and poor reporting of allocation concealment and blinding of participants, personnel and outcome assessments. Due to heterogeneity in the outcomes measured and measurement methods used, only limited data pooling was possible. 

Ginkgo biloba versus placebo

When we pooled data from two studies for the primary outcome tinnitus symptom severity, we found that Ginkgo biloba may have little to no effect (Tinnitus Handicap Inventory scores) at three to six months compared to placebo, but the evidence is very uncertain (mean difference (MD) ‐1.35 (scale 0 to 100), 95% confidence interval (CI) ‐8.26 to 5.55; 2 studies; 85 participants) (very low‐certainty). Ginkgo biloba may result in little to no difference in the risk of bleeding or seizures, with no serious adverse effects reported in either group (4 studies; 1154 participants; low‐certainty).

For the secondary outcomes, one study found that there may be little to no difference between the effects of Ginkgo biloba and placebo on tinnitus loudness measured with audiometric loudness matching at 12 weeks, but the evidence is very uncertain (MD ‐4.00 (scale ‐10 to 140 dB), 95% CI ‐13.33 to 5.33; 1 study; 73 participants) (very low‐certainty). One study found that there may be little to no difference between the effects of Ginkgo biloba and placebo on health‐related quality of life measured with the Glasgow Health Status Inventory at three months (MD ‐0.58 (scale 0 to 100), 95% CI ‐4.67 to 3.51; 1 study; 60 participants) (low‐certainty). Ginkgo biloba may not increase the frequency of other adverse effects (gastrointestinal upset, headache, allergic reaction) at three months compared to placebo (risk ratio 0.91, 95% CI 0.52 to 1.60; 4 studies; 1175 participants) (low‐certainty). None of the studies reported the other secondary outcomes of tinnitus intrusiveness or changes in depressive symptoms or depression, anxiety symptoms or generalised anxiety.

Gingko biloba with concurrent intervention versus concurrent intervention only

One study compared Ginkgo biloba with hearing aids to hearing aids only. It assessed the mean difference in the change in Tinnitus Handicap Inventory scores and tinnitus loudness using a 10‐point visual analogue scale (VAS) at three months. The study did not report adverse effects, tinnitus intrusiveness, changes in depressive symptoms or depression, anxiety symptoms or generalised anxiety, or health‐related quality of life. This was a single, very small study (22 participants) and for all outcomes the certainty of the evidence was very low. We were unable to draw meaningful conclusions from the numerical results.

Authors' conclusions

There is uncertainty about the benefits and harms of Ginkgo biloba for the treatment of tinnitus when compared to placebo. We were unable to draw meaningful conclusions regarding the benefits and harms of Ginkgo biloba when used with concurrent intervention (hearing aids). The certainty of the evidence for the reported outcomes, assessed using GRADE, ranged from low to very low. Future research into the effectiveness of Ginkgo biloba in patients with tinnitus should use rigorous methodology. Randomisation and blinding should be of the highest quality, given the subjective nature of tinnitus and the strong likelihood of a placebo response. The CONSORT statement should be used in the design and reporting of future studies. We also recommend the use of validated, patient‐centred outcome measures for research in the field of tinnitus.

Author(s)

Magdalena Sereda, Jun Xia, Polly Scutt, Malcolm P Hilton, Amr El Refaie, Derek J Hoare

Abstract

Plain language summary

Ginkgo biloba herbal supplement for tinnitus

What is tinnitus?

Tinnitus is a symptom where people have a perception of sound without there being an external source. It is often described as a ringing, hissing, buzzing or whooshing sound. It is common, affecting between 5% and 43% of the general population, and its prevalence increases with age. For some people tinnitus is persistent and troublesome, and it may lead to sleep problems (insomnia), difficulty concentrating, difficulties in communication and social interaction, and anxiety and depression. Management can include education and advice, relaxation therapy, tinnitus retraining therapy (TRT), cognitive behavioural therapy (CBT), sound generators or hearing aids, and drug therapies. The herbal supplement Ginkgo biloba has also been used.

What did we want to find out?

We wanted to find out whether Ginkgo biloba reduces tinnitus severity and whether it has any unwanted or harmful effects.

What did we do? 

We searched for studies that looked at Ginkgo biloba compared to placebo ('dummy' treatment), no treatment or education/information alone in adults and children with tinnitus. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as how the studies had been done and how many people were involved.

What did we find? 

We found 12 studies (with a total of 1915 people who participated). Eleven studies compared the effects of Ginkgo biloba with placebo. One study compared the effects of Ginkgo biloba combined with hearing aids to hearing aids alone.

Main results 

When we combined the results of two studies that measured tinnitus severity in the same way we found that Ginkgo biloba may have little to no effect compared to placebo, but the evidence is very uncertain. We looked at four studies that recorded any serious harmful effects, all of which reported none, so Ginkgo probably does not result in any difference in risk compared to placebo. However, the included studies did not look at the potentially harmful effects of Ginkgo biloba when used alongside other drugs. There may not be any difference between Ginkgo biloba and placebo in the effect on tinnitus loudness, but this is very uncertain. We also found that there may not be any difference in other outcomes (health‐related quality of life and minor unwanted effects such as gastrointestinal upset, headache and allergic reaction). There is no evidence to suggest that Ginkgo biloba has an effect on tinnitus when compared to placebo.

We looked at the study that compared Ginkgo biloba combined with hearing aids to hearing aids alone. It assessed the difference in the change in tinnitus severity and loudness using a scale at three months. The study did not report any of the other outcomes we were interested in. This was a single, very small study (22 people) and the evidence was very uncertain. We were unable to draw meaningful conclusions from the findings of this study.

What are the limitations of the evidence?

Although we found 12 studies, half of them did not report outcomes that we were interested in. We were not able to combine the results from many of the remaining studies. We are not confident in the evidence for the effect on tinnitus severity of Ginkgo biloba compared to placebo. This is because some people dropped out of one study, only people over 60 were included, the studies were small and very few studies reported this important outcome. We have little confidence in the evidence about serious harmful effects because none were reported in either group and the studies may have had some problems in the way they were done. For tinnitus loudness we are not confident in the evidence because the study that measured this was very small, some people dropped out and only this one study reported this important outcome. We have little confidence in the evidence for health‐related quality of life and minor unwanted effects because the studies were small and may have had problems with the way they were done.

We are not confident in the evidence for the effects of Ginkgo in combination with hearing aids because the number of participants in the study was very small.

How up to date is this evidence?

The evidence is up to date to June 2022.

Author(s)

Magdalena Sereda, Jun Xia, Polly Scutt, Malcolm P Hilton, Amr El Refaie, Derek J Hoare

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Ginkgo biloba is commonly used as a food supplement for tinnitus and is also a popular first‐line treatment prescribed by general practitioners (GPs) and ENT physicians across Europe (Hall 2011). However, we did not find any evidence to support or refute the prescription of Ginkgo biloba for subjective tinnitus. There is uncertainty about the benefits and harms of Ginkgo biloba for the treatment of tinnitus when compared to placebo. The included studies did not investigate the potentially harmful interactions of Ginkgo biloba with other drugs (Posadzki 2012). 

In line with the lack of evidence for the effectiveness of Ginkgo biloba and potentially harmful interactions with other drugs, current tinnitus management guidelines recommend against its use for tinnitus treatment (Cima 2019; Tunkel 2014). The Multidisciplinary European Guideline for Tinnitus (Cima 2019) based their recommendation on the results of several systematic reviews, which either concluded that Ginkgo biloba was not effective (Hilton 2013; Rejali 2004), or highlighted the low methodological rigour of the included trials (von Boetticher 2011). The authors also highlighted that there was evidence that Ginkgo biloba can interact with other anticoagulant drugs to cause serious bleeding and worsen bleeding risk in patients with underlying clotting disorders (Posadzki 2012). Similarly, the American Academy of Audiology Clinical Practice Guideline recommended against the use of Ginkgo biloba for treating patients with persistent, bothersome tinnitus (Tunkel 2014). The above recommendation was based on variation in conclusions, methodological limitations and heterogeneity in the study protocols of the randomised controlled trials (RCTs) in addition to conflicting conclusions from systematic reviews. The guideline also referenced the evidence for serious side effects, which involve platelet inhibitory actions of Ginkgo biloba, particularly if taken along with other medications that impair coagulation (Posadzki 2012), with the recommendation to avoid use of Ginkgo biloba in older adults, in which the use of anticoagulants and analgesics is widespread. Other mentioned herb‐drug interactions included thiazide diuretics, which resulted in increased blood pressure, and trazodone, which results in increased sedation (Tunkel 2014).

It is unlikely that the aetiology of tinnitus is the same for every tinnitus sufferer. Ginkgo biloba has been shown to affect vascular permeability and neuronal metabolism. If a greater level of understanding and diagnostic accuracy can be reached about the different aetiologies of tinnitus, this may naturally highlight subgroups of tinnitus patients in whom further controlled trials of Ginkgo biloba are worth considering.

Implications for research 

Future research into the effectiveness of Ginkgo biloba in patients with tinnitus should use rigorous methodology. Randomisation and blinding should be of the highest quality, given the subjective nature of tinnitus and the strong likelihood of a placebo response. The CONSORT statement should be used in the design and reporting of future studies (CONSORT 2010).

We also recommend the development of validated, patient‐centred outcome measures for research in the field of tinnitus. Visual analogue scales have limited value in this regard because quantifying change using only a single item has inadequate measurement properties (e.g. internal consistency cannot be established and test‐retest scores are at greater risk of instability). Only three out of 12 studies included in this review used multi‐item questionnaires of tinnitus symptom severity, and only one used a measure of heath‐related quality of life. Other outcomes such as depression and anxiety were not measured. Only four of the studies reported adverse effects. In future trials, multi‐item questionnaires of tinnitus symptom severity, validated instruments measuring depressive symptoms or depression, anxiety symptoms or generalised anxiety and health‐related quality of life should also be used. 

Core outcome measures for adults with subjective tinnitus have been identified (Hall 2018a). For pharmacological interventions, these are tinnitus intrusiveness and loudness. None of the included studies assessed tinnitus intrusiveness, and while loudness was assessed in two out of the five included studies, the measurement methods varied. There is no standard test for tinnitus loudness, and psychoacoustic loudness matching and subjective rating methods are equally common. These measurement methods are generally applied, and findings interpreted, with the assumption that they measure the same underlying construct (i.e. that they have convergent validity). However, retrospective analysis of one randomised placebo‐controlled trial in 91 participants with subjective idiopathic tinnitus indicates otherwise (Hall 2017). Use of the core outcome set as a minimum standard for what should be assessed and reported in RCTs will facilitate comparison between studies and meta‐analyses (Tunis 2016).

Given the heterogeneity of tinnitus patients, future trials should assess and report baseline characteristics so that the risk of potential confounding factors can be better understood. Examples include tinnitus duration, tinnitus symptom severity, age, hearing loss and co‐morbidities since these might reasonably modify treatment success. Future trials might also consider, as a subgroup analysis, the differential effect of Ginkgo biloba on acute (i.e. less than three months duration) versus chronic (more than three months duration) subjective idiopathic tinnitus. Individual participant characteristics were poorly described in the included studies. All studies included in the current review recruited chronic tinnitus patients (more than three months). Only three included studies performed a sample size estimation (Drew 2001; Halama 1988; Rejali 2004). Future studies should seek to recruit an adequate sample size based on an appropriate power calculation for the primary outcome.

It was not possible to address the question of the effectiveness of Ginkgo biloba for tinnitus associated with cognitive insufficiency as only two studies included such groups of patients (Halama 1988; Napryeyenko 2009), with neither study including outcomes of interest to the current review, but it is a key area to consider for future development. Therefore, any future research into the effect of Ginkgo biloba on tinnitus must be careful to define its patient population with respect to cerebral function. It would be beneficial if further trials in cognitive insufficiency explicitly report the results for the subgroup of patients who have tinnitus at the outset of the study. 

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