A Comparative Analysis of the Efficacy of Ginkgo Biloba and Caroverine in the Management of Idiopathic Tinnitus

Abstract

Aim

The sound sensation that is experienced in the ears or brain and is unrelated to any external sources of stimulus is known as tinnitus. Tinnitus Functional Index (TFI) is used to establish the presence of the condition and determine symptom severity, its impact on the patient’s quality of life, thus in this study, we aim to compare the efficacy of caroverine and Ginkgo Biloba in the management of idiopathic tinnitus using TFI.

Methods

This clinical study was conducted in at a tertiary care hospital in North India, for a duration of one year, among patients with chronic tinnitus. The sample size for this study consisted of 60 patients in each of three groups (caroverine, gingko biloba, and multivitamin). Assessments of TFI and pure-tone audiometry were performed to evaluate the efficacy of the two medications. The information pertaining to the subjects was kept anonymous and confidential. During data analysis, an association was significant for p value < 0.05.

Results

The patients in three groups were matched for the age, gender and duration of tinnitus. At 6 months of medication with Ginkgo Biloba, patients experienced a significant (p < 0.0001) decrease of 50.0% in tinnitus of moderate severity, and a complete resolution of severe tinnitus symptoms with a percentage change of -100.0%.

Conclusion

In our study, Ginkgo Biloba Group has significantly improved the severity of idiopathic tinnitus. Tinnitus has diverse underlying mechanisms, can be a symptom of various underlying diseases, and is challenging to measure. Further research is warranted to validate and explore these treatment options further.

Introduction

Tinnitus, a condition characterized by a ringing, buzzing, or hissing sound in the absence of external stimuli, is derived from the Latin word “tinnire.” Despite significant advancements in the field of medicine, tinnitus remains a perplexing phenomenon for clinicians. It is classified into subjective and objective types [1]. Objective tinnitus, which is uncommon, involves the perception of actual sounds resulting from internal biological activity, such as vascular turbulence or muscle spasms in the middle ear, Eustachian tube, or soft palate [2]. On the other hand, subjective tinnitus, the most prevalent form, refers to the perception of phantom sounds without any identifiable external source [3]. Globally, an estimated 15–20% of the population suffers from tinnitus, which, when severe, significantly impairs quality of life, affecting sleep, concentration, emotional well-being, and social interactions, and interfering with daily activities [4].

The TFI was developed to provide a scaling of tinnitus severity, an identification of tinnitus domains with impact on the tinnitus severity, and a responsive measurement of change in tinnitus severity [5]. Additionally, audiologic diagnostics, investigation of tinnitus characteristics (such as sensation, frequency, and intensity), and the use of laboratory and imaging tests are essential to identify hearing impairments and potential changes in efferent and afferent pathways, ruling out retrocochlear lesions [5].

The primary goal of tinnitus treatment is to alleviate symptoms and associated distress, although there are no universally accepted treatment protocols. Pharmacotherapy is one approach used to manage tinnitus, and a substantial body of literature exists on the subject [5]. The treatment of tinnitus remains a challenge due to its multifactorial nature and diverse etiological factors. Current treatment approaches include hearing aids, counselling, supportive therapy (e.g., tinnitus retraining therapy), and various medications such as vasodilators, corticosteroids, anticonvulsants, spasmolytics, lidocaine, benzodiazepines, Ginkgo Biloba preparations, and caroverine [6].

Caroverine is a medication with spasmolytic properties that functions by blocking calcium, non-NMDA, and NMDA glutamate receptors [7]. To ensure effective absorption, caroverine is typically administered intravenously or locally since oral administration has limited uptake. It is believed that cochlear synaptic tinnitus results from a disruption in the synaptic activity of NMDA or non-NMDA receptors on the afferent dendrites of spiral ganglion neurons [8].

The active component of Ginkgo biloba, known as extract of Ginkgo biloba 761 (EGb-761), is obtained from extracts of the Chinese tree G. biloba. This extract contains flavonoids, terpenes, and vasoactive compounds. Ginkgo biloba extract has been utilized for the treatment of various conditions, including tinnitus, due to its vasodilating and antioxidant properties [9]. Research studies have demonstrated that Ginkgo biloba can alleviate tinnitus symptoms, particularly in individuals with a short duration of symptoms [10]. Furthermore, a study conducted on rats showed that the administration of Ginkgo biloba reduced the behavioral manifestations of tinnitus induced by salicylate [11].

Considering that idiopathic tinnitus is the prevailing form of tinnitus and there is a dearth of research in the Indian population regarding this particular type, our study was conducted to assess the efficacy of Ginkgo Biloba in treating idiopathic tinnitus. Additionally, we aimed to compare its effectiveness with another treatment option, namely caroverine.

Materials and Methods

Study Setting and Design

This clinical study was conducted in the department of otorhinolaryngology at a tertiary care hospital in North India. The study duration was one year, from June 2021 to May 2022. The study focused on patients aged 18 years and above, of either sex, who presented with chronic tinnitus. The study design employed an open labelled randomized controlled trial, which is a well-established research design for comparing treatment interventions.

Study Population and Sample Size

The sample size for this study consisted of 60 patients in each of the two research groups and 60 patients in the control group. The determination of the sample size was performed utilizing power analysis software (Epi Info 7; CDC, Atlanta) with a 5% margin of error, a power of 0.8, and an effect size of 0.8. By including an adequate number of participants, the study aimed to ensure sufficient statistical power to detect significant differences between the treatment groups.

Inclusion and Exclusion Criteria

The inclusion criteria for participant selection in this study encompassed patients with tinnitus of either early or late onset, absence of psychiatric disorders, noise-induced hearing loss (NIHL) with tinnitus, and cochlear and retrocochlear pathology. These criteria aimed to include individuals who experienced chronic tinnitus without underlying psychiatric conditions or specific etiological factors. On the other hand, the exclusion criteria comprised tinnitus due to ototoxicity, tinnitus related to systemic, vascular, diabetes, anxiety, and depression disorders, tinnitus due to external middle ear causes, and pulsatile tinnitus or cerebellopontine angle tumors. Patients meeting any of these exclusion criteria were not included in the study to ensure a more homogeneous study population.

Intervention

Participants were randomly assigned to one control group and two research groups. The first research group received a single dose of caroverine injection (10 ml in 100 ml of normal saline), followed by six months of twice-daily caroverine capsule administration. The second research group received Ginkgo Biloba 120 mg twice a day for six months. The control group, which served as a reference, received multivitamins for the same duration. These interventions were chosen based on their potential efficacy in the management of idiopathic tinnitus.

Data Tool and Collection

Data collection involved several methods to comprehensively evaluate the participants’ tinnitus symptoms and treatment outcomes. Firstly, detailed history taking was conducted to gather relevant information about the participants’ tinnitus experiences. This was supplemented by subjective assessment using the Tinnitus Functional Index (TFI) questionnaire consists of 25 questions divided into eight subgroups: intrusive, sense of control, cognitive interference, sleep, auditory difficulties, QoL, relaxation and emotional distress. Furthermore, each answer is graded on a five-point scale to reflect the severity of tinnitus: no problem (0–18), a small problem (18–31), a moderate problem (32–53), a big problem (54–72) and a very big problem (73–100) [12]. In our study for analysis purpose, we reflected the severity of tinnitus by clubbing no problem (0–18) and a small problem (18–31) as Mild grade of tinnitus, a moderate problem (32–53) as Moderate grade of tinnitus, and a big problem (54–72) and a very big problem (73–100) as Severe grade of tinnitus. Additionally, clinical examinations were performed to assess any physical abnormalities or underlying conditions contributing to tinnitus. When necessary, auditory assessments and imaging procedures, such as pure-tone audiometry and imaging scans, were conducted to obtain objective data on hearing function and potential anatomical abnormalities. During pure-tone audiometry, sounds ranging from 0 to 16,000 Hz, were presented to the affected ear of the patients and they were asked to match their tinnitus to the nearest frequency (tinnitus matching), based on which the patients were divided into four categories. Patients were routinely monitored every 15 days for a period of six months to track their progress and treatment response. Assessments of TFI and pure-tone audiometry were performed before and after therapy every three months to evaluate the comparative efficacy of the two medications.

Data Analysis

The collected data were subjected to appropriate statistical analysis using IBM SPSS Statistics for Windows, Version 22.0 (IBM Corp. Armonk, NY, USA) to assess the efficacy of the medications in managing idiopathic tinnitus. Descriptive statistics (frequency, percentage [%], mean, standard deviation [SD]), was used to present the categorical and quantitative data for the three groups. Comparative analyses (Chi-square test, ANOVA, paired T-test, and Mc-Namer) were employed to determine any significant differences between the treatment groups and the control group. All tests (two tailed) were performed at a 5% level of significance; thus, an association was significant if the p value < 0.05.

Ethical Consideration

Ethical approval for the study was obtained from the relevant institutional review board or ethics committee, ensuring compliance with ethical guidelines and principles (Approval number: SMSR/2021/22/2RCT). Informed consent was obtained from all participants, highlighting the voluntary nature of their participation and guaranteeing their rights to privacy and confidentiality. The patients were provided with information by the treating physician regarding the purpose of the study, the chosen methodology, and the potential advantages and risks associated with participating in the study. The study design and procedures aimed to prioritize the well-being and safety of the participants while conducting rigorous scientific research.

Results

In present study, to determine if caroverine, gingko biloba, or a placebo is more effective at reducing tinnitus, 180 patients were randomly assigned to one of three groups, with 60 in each group. In terms of age groups, the majority of patients in all groups were in the < 40 years and 40–60 years categories, with relatively smaller proportions in the > 60 years category. The mean age was similar across the treatment groups, with Caroverine Group having a mean age of 47.03 ± 8.96 years, Gingko Biloba Group having 48.83 ± 11.37 years, and Multivitamins Group having 47.90 ± 10.52 years. When examining gender distribution, there were slightly more females than males in all three groups, with varying percentages. Specifically, the Multivitamins Group had the highest proportion of females at 55.0% (33/60), followed by the Gingko Biloba Group at 48.3% (29/60), and the Caroverine Group at 45.0% (24/60). The analysis revealed that there were no significant associations or differences (p > 0.05) observed among the treatment groups (Caroverine, Gingko Biloba, and Multivitamins) with idiopathic tinnitus for both age groups and gender and were matched for age and gender (Table 1).

Table 1.

Baseline characteristics of the patients in caroverine group, Gingko Biloba group and control group (multivitamins)

Variables	Number (%)			P value
	Caroverine Group (n = 60)	Gingko Biloba Group (n = 60)	Multivitamins Group (n = 60)
Age group
< 40 years	30 (50.0)	28 (46.7)	27 (45.0)	0.910
40–60 years	24 (40.0)	23 (38.3)	26 (43.3)
> 60 years	6 (10.0)	9 (15.0)	7 (11.7)
Mean age (in years)	47.03 ± 8.96	48.83 ± 11.37	47.90 ± 10.52	0.635
Gender
Male	27 (45.0)	31 (51.7)	36 (60.0)	0.257
Female	33 (55.0)	29 (48.3)	24 (40.0)

Regarding the duration of tinnitus, a majority of participants in all three treatment groups had a tinnitus duration of less than 6 months, with the Caroverine group having 15 patients (25.0%), the Gingko Biloba group having 17 patients (28.3%), and the Multivitamins group having 24 patients (40.0%). The mean duration of tinnitus was also calculated for each treatment group, with the Caroverine group having a mean duration of 8.36 ± 6.08 months, the Gingko Biloba group having a mean duration of 9.06 ± 7.28 months, and the Multivitamins group having a mean duration of 9.79 ± 7.85 months. The findings indicate that the distribution of tinnitus duration and mean duration is similar among the treatment groups (p < 0.05). The distribution of tinnitus sites also did not show any significant differences (p < 0.05). These findings suggest that the treatment groups have comparable characteristics in terms of tinnitus duration and site (Table 2).

Table 2.

Comparison of tinnitus characteristics of the patients in Caroverine group, Gingko Biloba group and control group (multivitamins)

Variables	Number (%)			P value
	Caroverine Group (n = 60)	Gingko Biloba Group (n = 60)	Multivitamins Group (n = 60)
Duration of tinnitus (in months)
< 6 months	15 (25.0)	17 (28.3)	24 (40.0)	0.247
6–9 months	17 (28.3)	11 (8.3)	10 (16.7)
9–12 months	22 (36.7)	22 (36.7)	15 (25.0)
> 12 months	6 (10.0)	10 (16.7)	11 (18.3)
Mean duration of tinnitus (in months)	8.36 ± 6.08	9.06 ± 7.28	9.79 ± 7.85	0.547
Site of Tinnitus
Left	15 (25.0)	17 (28.3)	14 (23.3)	0.901
Right	12 (20.0)	11 (18.3)	15 (25.0)
Bilateral	33 (55.0)	32 (53.4)	31 (51.7)

The decreased hearing was noticed among 31.7% of patients (19/60) in Caroverine group, 23.3% of patients (14/60) in the Gingko Biloba group, and 23.3% of patients (14/60) in the Multivitamins group and the distribution of patients with decreased hearing in three groups also did not show any significant differences (p < 0.05). It was found that among all patients the mode of onset of hearing loss was insidious in nature and progression of hearing loss was continuous in nature.

In the Caroverine Group, the percentage change in tinnitus severity was 38.9%, indicating an improvement. The Moderate category in this group showed a decrease of 9.7%, indicating some improvement. However, the Severe category had a of 36.4% in tinnitus severity, although the change was not statistically significant (p > 0.05). Moving to the Gingko Biloba Group, there was a substantial increase in tinnitus severity for the Mild category with a percentage change of 207.1%, the Moderate category experienced a significant decrease of 50.0% in tinnitus severity, while the Severe category had a complete resolution of tinnitus symptoms with a percentage change of -100.0%, which was highly statistically significant (p < 0.0001). For the Multivitamins Group, the Mild category had a small increase of 13.3% in tinnitus severity, the Moderate category showed a decrease of 6.3% in tinnitus severity, while the Severe category had no change (0.0%) and it was not statistically significant (p > 0.05) (Table 3).

Table 3.

Comparison of TFI score (pre and post treatment) among patients in caroverine group, Gingko Biloba group and control group (multivitamins)

TFI score	Pre-Treatment Number (%)	Post Treatment Number (%)	% Change in Tinnitus Severity	P value
Caroverine Group
Mild	18 (30.0%)	25 (41.7%)	38.9%	0.336
Moderate	31 (51.7%)	28 (46.7%)	-9.7%
Severe	11 (18.3%)	7 (11.4%)	-36.4%
Gingko Biloba Group
Mild	14 (23.3%)	43 (71.7%)	207.1%	< 0.0001
Moderate	34 (56.7%)	17 (28.3%)	-50.0%
Severe	12 (20.0%)	0 (0.0%)	-100.0%
Multivitamins Group
Mild	15 (25.0%)	17 (28.3%)	13.3%	0.909
Moderate	32 (53.3%)	30 (50.0%)	-6.3%
Severe	13 (21.7%)	13 (21.7%)	0.0%

Before treatment, there were no significant differences in hearing thresholds among the groups (p > 0.05) for both right ear and left ear. After, the Gingko Biloba Group showed a statistically significant (p < 0.05) improvement in hearing compared to the pre-treatment measurements in both right ear (Pre: 35.27 ± 15.01; and Post: 30.09 ± 11.42), and left ear treatment (Pre: 36.89 ± 14.32; and Post: 30.99 ± 11.54). The Caroverine Group and Multivitamins Group did not exhibit significant changes in hearing thresholds after treatment (p > 0.05) in both right ear and left ear (Table 4).

Table 4.

Comparison of improvement in hearing in pure tone audiometry (pre and post treatment) among patients in caroverine group, Gingko Biloba group and control group (multivitamins)

Mean Pure Tone Audiometry (in dB)	Mean ± SD			P value
	Caroverine Group (n = 60)	Gingko Biloba Group (n = 60)	Multivitamins Group (n = 60)
Right Ear
Pre-Treatment	36.27 ± 15.37	35.27 ± 15.01	37.22 ± 14.61	0.776
Post Treatment	35.12 ± 15.25	30.09 ± 11.42	35.18 ± 14.57	0.072
P value	0.681	0.035	0.445	-
Left Ear
Pre-Treatment	36.67 ± 13.18	36.89 ± 14.32	37.53 ± 13.99	0.939
Post Treatment	35.24 ± 12.94	30.99 ± 11.54	36.09 ± 14.13	0.071
P value	0.548	0.014	0.575	-

Discussion

The aim of this study was to compare the effectiveness of caroverine, gingko biloba, and a placebo in reducing tinnitus symptoms. A total of 180 patients were randomly assigned to one of three groups, with 60 patients in each group. The distribution of age groups showed that the majority of patients in all groups were in the < 40 years and 40–60 years categories, with smaller proportions in the > 60 years category. The mean age was similar across the treatment groups, indicating that age was well-matched among the participants and similar pattern was reported in the study by Cooper et al., [13].

Similarly, the gender distribution was relatively balanced, with slightly more females than males in all three groups. A similar pattern was seen in the study by Coles et al., where females (57.5%) are more commonly affected by the condition compared to males (42.5%) [14].

In our study, the analysis did not reveal any significant associations or differences among the treatment groups in terms of age groups and gender. This suggests that the groups were comparable and that any observed effects can be attributed to the treatments rather than demographic factors.

In the Caroverine Group, the percentage change in tinnitus severity was 38.9%, indicating an improvement. The Moderate category in this group showed a decrease of 9.7%, indicating some improvement. However, the Severe category had a of 36.4% in tinnitus severity. These results were consistent with the working theory on the origins of cochlear synaptic tinnitus. Previous studies demonstrated that caroverine acted as a potent competitive antagonist of the AMPA receptor and, at higher doses, a non-competitive antagonist of the NMDA receptor [15, 16]. Denk et al., observed inconsistent outcomes when treating tinnitus patients with caroverine [17]. In a separate study, Ehrenberger et al., examined the impact of caroverine on tinnitus patients over an extended period. Initially, they achieved positive results in 63% of participants through intravenous infusion of caroverine [18].

In our study, the Gingko Biloba Group, there was a substantial increase in tinnitus severity for the Mild category with a percentage change of 207.1%, the Moderate category experienced a significant decrease of 50.0% in tinnitus severity, while the Severe category had a complete resolution of tinnitus symptoms with a percentage change of -100.0%. Radunz et al., Meyer et al., and Figueiredo, et al., have reported on the effectiveness of Ginkgo biloba [19–21]. The results confirm the findings of a previous study by Zeman et al., which showed that a change of at least seven points in the THI score indicates a clinically significant improvement [22]. Jiang et al., reported a significant reduction in tinnitus (RR = 0.39, 95% CI = 0.24–0.65, p < 0.01, total n = 1,323) in the GBEs group compared to the control group [23]. Tan et al., indicated a lower occurrence of tinnitus in the GBEs group compared to the placebo group. Overall, EGb 761^® was superior to placebo, with a weighted mean difference for change from baseline, calculated in meta-analyses using random effects models, of -1.06 (95% CI: -1.77, -0.36) for tinnitus (p = 0.003) [24].

Another study by Raja et al., compared the effectiveness of Ginkgo biloba and caroverine in managing idiopathic tinnitus. It was reported that a significant reduction in tinnitus (63.3% and 60%) was observed, along with improvements in hearing thresholds and overall quality of life of the patients [25]. Similarly, a randomized double-blind clinical trial by Procházková et al., compared Ginkgo biloba in patients with sub-chronic or chronic tinnitus and it was found effective in reducing tinnitus-related noise and irritation, leading to overall improvement in the patients’ health [26].

Study by Drew et al., found that the Ginkgo preparation yielded comparable, albeit modest, improvements in the occurrence and intensity of tinnitus when compared to the placebo [27]. Several randomized controlled trials (RCTs), including those conducted Han et al., and Rejali et al., reported negative outcomes [28, 29]. Additionally, numerous studies on the subject lacked evaluability [30, 31]. A recent review, which served as an update of a Cochrane Review, evaluated multiple recent RCTs involving a total of 6,000 patients to determine the effectiveness of Ginkgo biloba. However, no evidence supporting its efficacy was found [32].

Common side effects of Ginkgo biloba include mild gastrointestinal disturbances (e.g., stomach pain, changes in bowel habits), and products containing Ginkgo biloba may induce headaches. On the other hand, adverse effects such as dizziness, gastrointestinal discomfort, allergic reactions, and an elevated risk of bleeding were documented [10, 11, 29, 32].

Limitations

The study was conducted in a single tertiary care hospital in North India. This limits the generalizability of the findings to other settings and populations, as results may vary in different geographical regions or healthcare systems. The study evaluated the effectiveness of treatments over a period of six months. However, the long-term effects and sustainability of the observed changes in tinnitus severity were not assessed. The study relied on subjective measures, such as the Tinnitus Case History Questionnaire (TCHQ), to assess tinnitus severity and treatment outcomes. Self-reported measures are susceptible to biases, including recall bias and individual interpretation, which may affect the accuracy and reliability of the results. Further research with extended follow-up periods would be beneficial. Further research addressing these limitations would enhance our understanding of the efficacy and limitations of the evaluated treatments for tinnitus management.

Conclusion

In conclusion, this study compared the effectiveness of caroverine, gingko biloba, and a placebo in reducing tinnitus symptoms. this study provides preliminary evidence that Gingko Biloba may be more effective in reducing tinnitus severity and improving hearing compared to caroverine and multivitamins. However, further research is needed to investigate the long-term effects and optimal dosages of Gingko Biloba for tinnitus treatment. The findings also highlighted the need for more effective treatments for tinnitus and the importance of considering individual characteristics, such as age, gender, tinnitus duration, and hearing loss, when evaluating treatment outcomes.

Funding

None.

Declarations

Conflict of Interest

Nil.