Can antioxidant supplementation reduce discomfort and intensity of sound in people with tinnitus?
Study under review: The Effect of Antioxidant Supplementation in Patients with Tinnitus and Normal Hearing or Hearing Loss: A Randomized, Double-Blind, Placebo Controlled Trial
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Tinnitus is defined as a condition during which a person hears sound that isn’t caused by an external source. The sound most people with tinnitus describe is a steady, high-pitched ringing, but the sound has also been described as continuous or intermittent whistling, static, whooshing, musical noise, or buzzing. Approximately 1 in 10 adults in the U.S. experienced at least one bout of tinnitus over the course of a year, with just over a third of those reporting chronic problems. If tinnitus is persistent and intolerable or extremely bothersome, it can cause functional impairment in thought processing, emotional state, hearing, sleep, and concentration.
There are two general types of tinnitus. Objective tinnitus (about 5% of cases) refers to sounds that are able to be heard with external instruments, such as a stethoscope. This type of tinnitus is usually caused by damage to the bones or vasculature of the ear. Subjective tinnitus (about 95% of cases) refers to sounds that cannot be heard from the outside and is thought to be caused by damage to the neuronal system of the ear. Figure 1 provides more detail about the differences between these types.
Oxidative stress has been proposed as one of the underlying causes of tinnitus. Oxidative stress is a term used to describe an imbalance in reactive oxygen species (ROS), which are formed in the body as a result of normal metabolism. Healthy cochlear tissues contain vitamins and enzymes as a part of the antioxidant defense system. Oxidative stress can develop if antioxidant defense systems in the inner ear are not able to adequately detoxify ROS. Excess ROS can have detrimental effects on cellular constituents like lipids, proteins, and DNA. There is evidence showing that oxidative stress may lead to oxidative injuries in the acustico-vestibular (hearing and balance) system. Therefore, it makes some sense that supplementation with antioxidants may help alleviate the damage and symptoms associated with tinnitus.
Biomarkers associated with oxidative stress have been detected at higher levels in people with tinnitus, in conjunction with reduced antioxidant activity. There is limited and conflicting data regarding the efficacy of antioxidant supplementation for controlling tinnitus. A study using Ginkgo biloba, a good source of flavonoids, showed that this supplement reduced subjective discomfort and intensity of tinnitus. Another study showed that 18 weeks of supplementation with antioxidants and phospholipids alleviated oxidative stress and decreased the discomfort and intensity of tinnitus. On the other hand, other studies using zinc supplementation and antioxidant therapy (Ginkgo biloba, α-lipoic acid + vitamin C, papaverine hydrochloride + vitamin E) did not show any benefits.
Based on the proposed oxidant stress mechanism of the etiology of tinnitus, alongside the results of supporting studies, it is reasonable to hypothesize that antioxidant therapy may be effective in improving tinnitus parameters and discomfort, and impact biomarkers of oxidative stress. The researchers aimed to determine if a commercially available multivitamin-multimineral supplement containing phytochemicals along with the antioxidant alpha-lipoic acid (ALA) would improve tinnitus parameters and subjective discomfort in people with tinnitus, alongside biomarkers of oxidative stress.
Tinnitus is a condition characterized by the perception of sound with no external stimulus. It has been estimated that around 4% of adults in the U.S. have chronic tinnitus. Oxidative stress may be one of the molecular mechanisms that underlies the etiology of tinnitus. It has been proposed that antioxidant supplements may help alleviate the symptoms associated with tinnitus. This study examined the effects of a multi-ingredient antioxidant and vitamin/mineral supplement in people with tinnitus.
This was a preregistered, randomized, double-blind, placebo-controlled trial that was designed to examine the influence of antioxidant supplementation on tinnitus discomfort and loudness. The study also looked at changes in the frequency of tinnitus, impact of tinnitus on lifestyle, hearing thresholds, and biomarkers of oxidative stress. The researchers enrolled 70 males and females between the ages of 25 and 75 who had been experiencing tinnitus for at least six months. People who developed tinnitus due to physical trauma (e.g., a head or neck injury, sudden extremely loud noises), suddenly lost their hearing, or were taking drugs that could induce tinnitus (e.g., some chemotherapy drugs, loop diuretics, aminoglycoside antibiotics, high-dose aspirin) were excluded. Tinnitus parameters (e.g., duration of condition, amount of time sound is perceived, loudness, frequency, age of onset) were similar between groups at the start of the study.
The authors conducted a power analysis to determine how many participants would be required to have a 95% chance of getting a statistically significant difference between the placebo and treatment group in the case of a true effect (i.e., to achieve 95% power). They found that they needed 68 total participants. While the authors didn’t explicitly say what variable they used to calculate power, they did declare tinnitus loudness to be the primary outcome in another section of the paper. Loudness was also a primary outcome in the preregistration alongside the Tinnitus Handicap Inventory Questionnaire score, which ranges from 0 to 100 and assesses the impact of tinnitus on daily life.
The participants were randomly allocated into either an antioxidant treatment or placebo group. The antioxidant treatment group was asked to consume one multivitamin-multimineral tablet containing 500 milligrams of grapeseed extract once per day with a meal and one 500 milligram tablet of ALA (a strong antioxidant) two times per day on an empty stomach for three months. The multivitamin-multimineral tablet was a commercially available supplement that contained a mixture of 25 vitamins and minerals, including several antioxidants like vitamins E and C. The doses of vitamins and minerals were consistent with or greater than the Recommended Dietary Allowances and Adequate Intakes (RDA) but did not exceed the tolerable upper intake levels. The placebo group was asked to consume three placebo tablets per day at the same time points as the treatment group. To assure compliance, each study participant was seen monthly and blood was monitored for levels of vitamins and minerals.
Prior to and following the intervention, participants received a baseline assessment consisting of anthropometric measures (height and weight). They also received a battery of audiometric measures, including standard hearing tests and assessments for tinnitus, such as the Minimum Masking Level (MML), which determines the minimum intensity necessary to mask a person’s tinnitus; a frequency pitch match test, which determines the frequency pitch of tinnitus; and a loudness matching test, which determines the loudness of tinnitus. Tinnitus discomfort measures using questionnaires were also taken.
There were also several measurements taken not directly related to hearing. These included psychological measures (using Center for Epidemiological Studies-Depression and Hospital Anxiety and Depressions scales), physical activity measures (using a self-administered form of the International Physical Activity Questionnaire), and dietary assessment (using a 24-hour recall for three days, a Food Frequency Questionnaire, and assessment of adherence to a Mediterranean dietary pattern).
Finally, blood samples were analyzed for vitamins and minerals and biomarkers of oxidative stress, including serum total antioxidant capacity (TAC), serum superoxide dismutase (SOD), and oxidized low-density lipoprotein (oxLDL).
This was a registered, randomized, double-blind, placebo-controlled, parallel group clinical trial in 70 participants that was designed to examine antioxidant supplementation’s influence on tinnitus discomfort and loudness. The study also looked at changes in frequency of tinnitus, psychological effects, hearing thresholds, and biomarkers of oxidative stress. Participants received either a multivitamin/multimineral with grape seed extract and ALA supplement, or a placebo once daily for three months.
Treatment with the antioxidant supplements was found to decrease loudness by 14.2 decibels (db) and MML from baseline to post-measure by 14.5 db. The placebo group also experienced lesser decreases of 6.7 and 1.6 db, respectively. But even though the placebo group also experienced improvements, the difference between the treatment and placebo groups was still strongly statistically significant. The researchers do not address why there were decreases in these indicators in the placebo group, but some possible reasons include placebo effects, random noise, or the group naturally getting a bit better over time because they tended to have somewhat extreme tinnitus to start with—a phenomenon known as regression to the mean.
Regardless of the reasons for the placebo group’s improvement, the treatment group’s decreases were still about two- and seven-fold greater for loudness and MML, compared to placebo. The supplementation protocol also reduced the measure of subjective discomfort, which was the co-primary outcome in this study’s preregistration, and the Tinnitus Handicap Inventory score, by about 20%, a significant drop compared to placebo. The supplement protocol’s impact on these outcomes are summarized in Figure 2. Changes in other measures of subjective discomfort were not statistically significant between treatment and control.
To put the results into perspective, consider what the sound measures represent. The sound level for normal conversation is about 60 db, while a soft whisper is about 30 db. The sound level for a refrigerator humming is about 45 db, the background conversation in a restaurant is around 60 db, and a running lawnmower is about 90 db. Therefore, in the antioxidant group, if the tinnitus loudness started at a mean level of 45 db before the treatment and decreased to a mean level of 30.8 db following the treatment, this would be equivalent to a change in sound from a refrigerator running to a soft whisper. The MML, which represents the lowest level of sound needed to mask a patient’s tinnitus, decreased from a mean level of 57.9 db (roughly equal to the background noise in a restaurant) to a mean level of 43.4 db (the loudness of a running refrigerator).
Changes in serum total antioxidant capacity (TAC), SOD, and oxLDL were not significant between groups. This lack of clear effect is surprising, given the proposed key role of oxidative stress in the etiology of tinnitus. The researchers state that the lack of change may be due to the low doses of the antioxidant vitamins C and E in the supplement. It could also be that food-derived antioxidants were more influential in establishing a biomarker level than the antioxidant supplement.
Treatment with the antioxidant supplements was found to decrease loudness and MML from baseline to post-measure. Supplement treatment also reduced subjective discomfort. There were no changes in biomarkers of oxidative stress, which could be because the doses were not high enough in the supplement mixture.
The study has several strong suits, as well as a few concerning features. Let’s start with the strengths.
First, the measurements were well chosen. The measurements of tinnitus loudness, frequency, and MML, along with the questionnaires that assessed participant discomfort associated with tinnitus, were applied in accordance with the consensus for tinnitus patient assessment and treatment outcome measurement. This provides confidence that relevant outcomes were being measured in the study. In this population, the antioxidant supplement reduced tinnitus loudness and MML, which are indicators of sensory aspects of tinnitus. Also, the reduction in the Tinnitus Handicap Inventory score in the antioxidant group was clinically relevant.
However, there are also some weaknesses. One limitation isn’t so much due to the study design, but the way it was reported. The authors placed a strong emphasis on within-group differences when they reported the results. This isn’t ideal, since it ignores what is going on in the control group, and negates the benefits of having running a controlled trial in the first place. When reporting on what the authors found in this review, the Study Deep Dives editors shifted the focus to between-group differences.
Another limitation is that it’s impossible to tell which component(s) of the mixture were effective, or whether there was synergy going on and all of them were required for efficacy. More research is needed to determine which components of the mixture used in this study contributed to the observed benefits.
This limitation is amplified by the fact that there was no clear observed effect on oxidative stress. Remember that the authors had reason to believe that oxidative stress could play a role in tinnitus. This theory would have been supported if the supplement was shown to be effective and oxidative stress was significantly reduced. However, that’s not what happened. Instead, the supplement was effective for tinnitus, but there was no clear influence on oxidative stress. This raises the question of how the supplement exerted its effect. However, because so many ingredients were included in the supplement, the question cannot be answered as yet.
This study measured relevant parameters and found a statistically and clinically significant effect on tinnitus for this particular mixture of ingredients. However, there were some issues with the way the results were reported. More importantly, it’s impossible to say which ingredients of this supplement actually contributed to the observed effect, especially given the lack of a clear effect on oxidative stress. More research is needed to tease apart which ingredients work best for tinnitus.
This study suggests that an antioxidant supplementation containing a large array of vitamins, minerals, phytochemicals, and ALA (an antioxidant) taken for three months could decrease discomfort and intensity of tinnitus in people with a history of at least three months of persistent or recurring tinnitus not due to physical trauma or who were taking possibly tinnitus-inducing drugs. While people with tinnitus may experience a benefit after supplementing with this particular mixture, it’s not at all clear which particular components of this mixture actually contributed to the observed effect. More research is needed to confirm efficacy and to determine what works best.
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