Standardized Ginkgo Biloba Extract in the Treatment of Vertigo and/or Tinnitus: A Review of the Literature

Standardized Ginkgo biloba extract (GBE) is an established herbal treatment used for a variety of indications, including vertigo and/or tinnitus. The evidence base in human clinical studies for a clear benefit of GBE in vertigo and/or tinnitus is limited and contradictory due to poor reporting as well as variations in study quality and outcome measures used. The aim of this review is to identify and discuss the rationale for using GBE in the treatment of vertigo and/or tinnitus based on the known pleiotropic actions of GBE and the pathophysiology of vertigo and/or tinnitus. The rationale will be substantiated by a review of the literature in order to identify and evaluate clinical trials investigating the efficacy of GBE in individuals with vertigo and/or tinnitus. The review identified randomized controlled trials (RCTs) investigating the effectiveness of GBE in vertigo and/or tinnitus published in PubMed up to 1 January 2020. In total, 17 RCTs were included 8 of the 9 studies investigating tinnitus and/or vertigo/dizziness found improvements, and 6 of 8 included studies investigating solely tinnitus showed positive effects. Based on the known mechanisms of action of GBE as well as evidence from animal models and human clinical trials identified in this review, GBE is a rational alternative treatment that might provide benefits to individuals with vertigo and/or tinnitus. However, further well-defined RCTs in patients with defined pathological entities are necessary to further substantiate the beneficial effects of GBE for vertigo and/or tinnitus.


Introduction
Maintaining balance and orientation depend on input from the visual and proprioceptive systems, the inner ear, and integration in the brainstem vestibular nuclei and the cerebellum [1]. Dysfunction of any of these systems can cause disorders of balance and the sense of orientation, often leading to complaints of dizziness and/or vertigo [2].
Vertigo is the illusion of rotation, spinning, or swaying in the objects around or in the patients themselves [3]. Acute vertigo symptoms of the peripheral vestibular system are often associated with nausea, vomiting, sweating and pallor [4]. Many people with vertigo and/or dizziness complaints also experience emotional, memory, and self-perception problems, which are especially common in the elderly [2]. Vertigo and/or dizziness is a common complaint, with an estimated 1-year prevalence between 40% and 50% in adults [5] [6]. Vertigo can be tentatively classified as either vestibular or non-vestibular in origin. Dysfunction of the vestibular system (vestibular vertigo) accounts for about a quarter of dizziness complaints and has a 1-year prevalence of 5% and an annual incidence of 1.4% [7]. Despite the considerable personal and health care burden of dizziness and vertigo symptoms, a large percentage of the underlying disorders remain under diagnosed and, therefore, are probably insufficiently treated [8].
Tinnitus is the perception of sound in the ears or head without any external or internal acoustic stimulation, hence it is considered a symptom rather than a disease per se [9] [10]. If persistent and either intolerable or sufficiently bothersome, tinnitus and/or hearing loss can have a profound impact on quality of life (QoL), causing functional impairment in thought processing, emotions, hearing, sleep, and concentration [11] [12]. Tinnitus is typically classified as either subjective/sensorineural tinnitus, heard only by the affected person, or objective/somatic tinnitus [13]. Another possible distinction is acute versus chronic tinnitus; if persisting longer than a certain amount of time, conventionally between six and twelve months, it is usually regarded as "chronic", reflecting clinical experience that the phantom sound will persist [14]. Moreover, the etiology of tinnitus is often considered idiopathic, as 40% of patients report "no known events" associated with their tinnitus onset [9]. It is therefore a heterogeneous disorder with regard to its etiology, presenting symptoms, and perceptual characteristics [15].
Like vertigo, tinnitus is also a common problem in the general population, with prevalence estimates range from 4.6% to 30% [16]. The prevalence of tinnitus increases with age and the presence of hearing loss [17]. Using the Short Form Health Survey (SF-36), one study assessing QoL in 53 audiology patients reporting tinnitus showed that 43% also had impaired QoL, a high level of distress or both [18]. A U.S. cross-sectional analysis representative 12-month health survey evaluating 21.4 million American adults with tinnitus, reported that 27% experienced symptoms for more than 15 years and 36% had near-constant symptoms [16]. It is estimated that only about 50% of sufferers will discuss their tinnitus with a physician, and medications are recommended in less than half of these  [16]. Consequently, tinnitus also remains under diagnosed and insufficiently treated [16].
The ancient herbal extract from the leaves of the Chinese Ginkgo biloba tree, which contains about 250 different compounds involved in many different mechanisms, has shown beneficial effects in treatingneurodegenerative diseases like Alzheimer's, cardiovascular diseases, cancer, stress, memory loss, tinnitus, geriatric complaints like vertigo, age-related macular degeneration, and psychiatric disorders like anxiety disorder, adjustment disorder or schizophrenia [19] [20] [21] [22]. Most randomized controlled trials (RCTs) evaluating the effects of Ginkgo biloba to date have used the standardized dry leaf extract (GBE) EGb 761 and the similarly manufactured LI 1370. In accordance with regulatory requirements, the active components of both pharmaceutical-grade products contain 24% flavonoids, 6% triterpenes, and both GBEs are purified to contain less than 5 parts per million ginkgolic acids to avoid toxicity [23] [24] [25].
This review consists of two parts. In part one, we discuss the rationale for using GBE for the treatment of vertigo and/or dizziness and tinnitus based on the complex pathophysiology of these disorders as well as the known mechanism of actions of GBE. In part two, we examine the breadth of literature published to reveal the RCTs conducted in relation to the treatment of vertigo and tinnitus with GBE, with the aim of providing insights and guidance for physicians on where to focus their research.

Pathophysiology of Vertigo and/or Dizziness and Tinnitus
The major vestibular structures located in the inner ear include three semicircular ducts (lateral, anterior and posterior), and two otolith organs (saccule and utricle) [26]. The neuroepithelium of these peripheral vestibular organs are lined with hair cells that relay sensory impulses to the brainstem and the cerebellum [26]. Specific processingareas in the brainstem, cerebellum, and cerebral cortex integrate the sensory information from the peripheral vestibular organs, visual system, and proprioceptive system to allow for proper balance and orientation of the body in its environment [26]. Clear vision during head movements is maintained via an automated function called the vestibular ocular reflex (VOR) [1].  [28]. However, symptomatic improvement is not analogous with recovery of vestibular function, and the vestibular functional loss is often irreversible [4].
Tinnitus is a symptom that may be associated with dizziness and/or vertigo [29]. In some cases, it is associated with sensorineural hearing loss as a result of damage to the auditory system (24% of tinnitus cases occur due to abnormalities within the inner ear and vestibulocochlear nerve, 35% originate due to abnormalities in the acoustic pathway), although it can also be associated with other factors, such as some head injuries, exposure to certain drugs, nerve damage or blood-flow problems (41% of cases originate within the supratentorial structures of the brain) [30]. The current consensus is that tinnitus is a disorder involving a distributed network of peripheral and central pathways in the nervous system.
Though most cases are idiopathic, some tinnitus patients suffer with sensorineural tinnitus that might be caused by pathophysiological changes in either function or activity of the peripheral (i.e., changes in auditory input at the level of the cochlea and auditory nerve) or central auditory nervous systems [13].
Mazurek et al. (2007) showed that intensive noise exposure or ototoxic drugs can be a factor in the development of tinnitus [31]. Indeed, pathologic changes in cochlear neurotransmission, e.g. destruction of the hair cells in the inner ear by noise-induced hearing loss (NIHL) has been identified as one of the most frequent causes of sensorineural tinnitus [13]. While damage to the inner and outer hair cells in the inner ear often recovers after acute noise exposure, auditory nerve fibers to the inner hair cells appear more vulnerable [32]. Newer research also suggests that synapses between hair cells and cochlear neurons may be affected, which could lead to "hidden hearing loss" that is not detectable with standard audiometric methods (e.g. Liberman, M.C.) [33]. Detectable damage to the auditory periphery by itself seems neither sufficient nor required to give rise to chronic tinnitus, indicating extra-auditory modulation of the auditory sensation [15]. In addition, several observations suggest that tinnitus has neural correlates in the brain, regardless of peripheral damage that might trigger it [15] [34]. For example, in many cases, tinnitus persists after the transection of auditory nerve VIII, which destroys cochlear input to the brain [15] [35]. A proposed neurophysiological model hypothesizes that peripheral changes in input (deafferentation) causes plastic changes to occur, resulting in altered patterns of brain activity due to anatomic changes in the connectivity of central nervous system  [37]. Although the precise mechanism is unclear, several models are under discussion. The neurophysiological model postulates that tinnitus is associated with functional changes not only in the auditory cortex but also in non-auditory regions such as the limbic, frontal, and parietal areas [38]. The most recent model by Sedley et al. [39] is based on predictive coding, in which spontaneous activity in the subcortical auditory pathway constitutes a "tinnitus precursor" which is normally ignored as imprecise evidence against the prevailing percept of "silence". Extant models feature as contributory mechanisms acting to increase either the intensity of the precursor or its precision. If precision (i.e., postsynaptic gain) rises sufficiently then tinnitus is perceived.
Perpetuation arises through focused attention, which further increases the precision of the precursor, and resetting of the default prediction to expect tinnitus [39].

GBE Mechanism of Action
GBE has been shown to have neuroprotective effects, including improved energy supply by the mitochondria, antioxidative or radical capturing properties, and to improve cerebral perfusion (through reduction in blood viscosity) and glucose utilization [40]. Which mechanisms play the decisive role in the action of GBE in vertigo and vestibular compensation cannot be stated definitively. Depending on the pathogenetic background, both antioxidative properties and activation of cerebral metabolism may be possible as well as vigilance-enhancing and cognitive activation effects [41]. An influence of GBE on the vestibular system and vestibular compensation could be demonstrated in animal experiment models [42]- [47]. Vestibular compensation could be demonstrated morphologically by an increased new formation of synapses in the vestibular nuclei region of treated cats [44] and biochemically as an increase in protein synthesis in the region of the vestibular nuclei [47].
GBE has demonstrated several effects within the CNS that may enhance neuronal plasticity and neurotransmitter levels. For example, GBE effects have been reported, including, among others, protection of neuronal mitochondrial ATP synthesis in the presence of oxidative stress [48] [49], protection against oxidative damage in erythrocyte membranes [50], which consequently lowers blood viscosity and improves blood flow [51] [52] and neuroprotection through antiapoptotic activity [53] [54] [55] [56] [57].
These effects of GBE have been well documented in both animal and human studies, and may treat tinnitus by preventing free-radical damage to the cochlea, or increasing blood flow and ultimately improving the health of the inner ear [58] [59] [60]. GBE provided a statistically significant decrease in behavioral manifestation of tinnitus induced by sodium salicylate toxicity in a rat model [61]. In 9 Mongolian gerbils (Meriones unguiculatus) that displayed behavioral signs of subjective tinnitus, three weeks of daily oral GBE led to improvement in all 9 animals, with 7 of them showing complete relief of tinnitus [62]. After dis-Advances in Aging Research continuation of GBE treatment, tinnitus related behavior reappeared in all but one animal while auditory thresholds remained restored [62]. The authors suggested that a global inhibitory mechanism was involved to counteract tinnitus. Tian et al. (2013) showed that GBE prevents cisplatin-induced hearing loss in rats and enhanced the antiatherogenic effects of cisplatin by inhibiting the generation of reactive oxygen species [63]. Tziridis et al. (2014) investigated the effectiveness of prophylactic treatment with GBE for NIHL and development of tinnitus after noise trauma in an animal model. Results suggested that significant neuroplastic effects of GBE had an effect on auditory processing at the peripheral and central level of the auditory pathway as measured with behavioral and electrophysiological approaches [64]. The authors of this study proposed two main effects of GBE: 1) an increase in auditory brainstem activity leading to an increased thalamic input to the primary auditory cortex; and 2) an asymmetric effect on lateral inhibition in the primary auditory cortex [60] [64].

Identification of Relevant Studies
Relevant studies were identified by a systematic search in PubMed of the literature up to 1 January 2020. Studies were eligible for inclusion if they met predefined inclusion criteria: 1) employed a study design with no major methodological shortcomings or bias, e.g. RCT; 2) evaluated an identifiable, standardized GBE, the composition of which is adequately described; 3) treatment dosing and duration (≥12 weeks) were appropriate for the indication (tinnitus/vertigo); 4) enrollment of patients (inpatients or outpatients) suffering from vertigo of unknown etiology or not otherwise specified, or tinnitus as the primary or concomitant complaint; and 5) publication in English, French, German, Russian, Spanish, or Italian language. We excluded non-RCT designs (including cross-over designs), combination treatments, and non-human studies.

Search Strategy
RCTs of interest were identified by searching the PubMed database (up to 1 January 2020) using the search terms "Ginkgo" and "vertigo" or "tinnitus" in the title/abstract, and by requesting information on randomized controlled trials of any EGb 761 or LI 1370 GBE product on tinnitus or vertigo from a manufacturer. Reference lists of retrieved studies were searched by hand to ensure all potential RCTs were included. Initial screening was based on title and abstract reading. When there was uncertainty whether or not a record was relevant, the full text record was screened.

Efficacy of GBE in Vertigo
A RCT by Sokolova et al. (2014) showed that there was no statistically significant difference in vertigo treatment outcomes between GBE versus betahistine group, though GBE had a better tolerance profile [66].
Cesarani et al. (1998) reported that in the first month of therapy, vertigo and dizziness improved in patients treated with betahistinedihydrochloride and GBE to a similar extent [67]. Differences in side effects reported in a few patients Figure 1. PRISMA flowchart of articles screened for inclusion [114]. RCT: randomized controlled trial; GBE: Ginkgo biloba special extract.  suggest that betahistinedihydrochloride and GBE exert their effects at different equilibrium receptor sites. Moreover, GBE treatment consistently improved VOR [67]. It is however important to note that this is difficult to assess; also the improvement of this symptom does not necessarily mean that vestibular functions are restored.
In a much earlier study, Haguenauer et al. (1986) using EGb 761, showed that GBE treatment for 12 weeks was significantly superior compared to placebo with regard to the improvement in subjective vertigo symptoms, expressed as a reduction in intensity, frequency and duration of vertigo symptoms, and the associated impairments in daily life [68]. Overall, the difference in improvement between the 2 groups reached 85% at the end of the study (p < 0.001) [68]. No results were reported for the Romberg or Babinski-Weil tests, and other neuro-otological findings, e.g., spontaneous nystagmus. However in the caloric test, electronystagmographic findings showed normalization in 80% of those patients having pathological values on enrolment into the study under treatment with GBE vs. 57% of those who received placebo [68].
Usingcraniocorpographyto evaluate vestibular function, Claussen and Kirtane (1985) found GBE to have a positive effect on subjective dizziness symptoms and lateral body sway vs. placebo [69].

Efficacy of GBE in Vertigo/Dizziness and/or Tinnitus
In the five included RCTs, although the patients treated with GBE had mild to moderate dementia as their primary complaint, 92% reported associated neurosensory symptoms such as dizziness and/or tinnitus at baseline. An 11-point box scale was used to assess the presence and severity of tinnitus and dizziness as a secondary outcome measure in all trials. In all 5 trials, there was a mean reduction in tinnitus severity for the GBE treated patients compared to placebo.

Efficacy of GBE in Tinnitus
Of the 8 tinnitus studies included in our review, six studies reported positive benefits with GBE. Halama et al. (1988) showed that in the GBE group, a supe- tion with a hearing aid was effective regardless of patient's tinnitus duration [74]. The authors concluded that this result may be associated with GBE's mode of action, i.e., free radical scavenger activity, anti-inflammatory activity and enhanced neuronal plasticity that can reduce tissue and neurological damage [74].
Although Morgenstern and Biermann (1997) reported a larger regression of tinnitus loudness in the GBE vs. placebo group, the subjective impression change for the patients was not positively impacted [75].
In the earliest study, Meyer (1986) reported that GBE improved the condition of all the tinnitus patients, irrespective of the prognostic factor [76]. Two studies were negative with regard to GBE efficacy in tinnitus. Drew and Davies (2001) concluded that GBE is no more effective than placebo in treating tinnitus [77]. In 12 tinnitus patients treated with GBE, Polanski, et al. (2016) reported that there was no benefit from the use of GBE and other antioxidant agents for tinnitus in their study [78].

Discussion
In contrast to other Ginkgo biloba leaf preparations, the standardized EGb 761 and LI 1370 are considered pharmaceutically equivalent, are well-defined, and have documented efficacy in improving neurologic functions for a wide array of disorders, including cerebrovascular insufficiency [79], memory impairment in the elderly [80], Alzheimer's disease [81], multi-infarct dementia [82], depression [83], peripheral artery insufficiency/improved microcirculation [84] [85], venous insufficiency [86], and asthma [87] [88]. Other studies suggest GBE has potential efficacy in conditions such as tinnitus [76] and vertigo of undetermined etiology [68]. Standardized GBE as a herbal treatment in vertigo and/or tinnitus therefore deserves careful consideration by physicians because of evidence of the promising aforementioned benefits and well-documented tolerability, as well as the limited or complete lack of efficacy with conventional pharmacological agents for these conditions and the increasing patient demand for CAMs [89]. Moreover, given the high patient burden caused by tinnitus and/or vertigo, any therapy that can even moderately improve symptoms can have a considerable impact on QoL for many sufferers [90].  [95]. Notably, the exact 5 studies evaluated in this review for tinnitus and/or dizziness were previously identified and included in a meta-analysis reported by Spiegel et al. (2018). Based on the Jarad scale assessment of methodological quality, the authors judged that the 5 studies included in their meta-analyses had a low bias risk [21]. Overall, they showed that GBE was superior to placebo, with weighted mean differences for and any medical needs are essentially unmet [24]. Typical treatment options for tinnitus include noise masking, pharmaceuticals (tricyclic antidepressants, selective serotonin reuptake inhibitors, pentoxifylline, steroids, etc.), acupuncture, and cognitive behavioral therapy (CBT) [24] [104] [105]. Newer approaches include acoustic stimulation [106] [107] and neuromodulation, such asvagus nerve stimulation [108], transcranic magnetic stimulation, or neurofeedback [109].
Complementary and alternative medicine (CAM) such as herbal supplements, have also stepped into the void created by the lack of consistently effective therapies [89].
Vertigo and tinnitus follow a complex pattern of pathophysiological effects involving an ambiguous interplay between auditory and somatosensory systems, neuro-cognitive, and neuronal-emotional networks [110] [111]. These underlying processes remain poorly understood and require continued investigation. It Advances in Aging Research lactones (6%); these standardized products also contain less than 5 ppm of the allergenic component, ginkgolic acid [20] [112]. Details of the exact role of neuroplasticity and how exactly the active constituents of GBE act on CNS and cerebral recovery mechanisms considered as key processes in vestibular compensation is as yet not well understood and requires further investigation. Also, tinnitus has recently been shown to be a highly heterogeneous phenomenon that differs greatly between affected individuals. Origin of the percept, subjective manifestation (e.g., intensity, pitch, location), as well as related distress and other comorbid symptoms of tinnitus have thus been found to show considerable variability within the tinnitus group [113], making it highly likely that distinct subtypes of tinnitus may be identified in the future. As the underlying processes of many different tinnitus subtypes are not yet fully understood, the exact mode of action of GBE remains unknown. One of the key advantages of using a herbal medicine such as GBE for treating complex pathophysiological disorders is that it has a pleiotropic mechanism of action and is able to up-or down-regulate different signaling pathways [112].

Conclusion
GBE is the best-studied phytotherapy medicine to date with excellent tolerability in humans. Based on its known mechanisms of action as well as evidence from animal models and/or human clinical trials, EGb 761 and LI 1370 enable a rational alternative treatment that might provide benefit to individuals with vertigo and/or dizziness and tinnitus. The current consensus is that tinnitus and vertigo disorders involve a distributed network of peripheral and central pathways in the nervous system. Among its many functions, GBE has been shown to reduce vascular resistance, improve peripheral blood circulation and promote neuroprotection, which may positively benefit the pathophysiological changes that occur in patients with tinnitus. Further research into the etiology of vertigo and tinnitus is however important in order to improve our understanding of the pathophysiological mechanisms underlying these symptoms. The heterogeneous nature of tinnitus, in particular, requires more research to determine whether GBE can be of benefit to all patients. Additional trials with standardized research methodologies are also required to further assist physicians in their decision-making for patients with vertigo and/or dizziness and tinnitus symptoms.