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Does Melatonin Have Therapeutic
Use in Tinnitus?
Leah Merrick, RN, Dima Youssef, MD, Michelle Tanner, MS IV, and Alan N. Peiris, MD, PhD
Abstract: Melatonin, a hormone produced by the pineal gland, may
be a promising treatment option for tinnitus. The primary functions
of this hormone are believed to be the initiation and maintenance of
sleep because its secretions coincide with circadian rhythms. Some
investigators have noted that melatonin may alleviate subjective
symptoms of tinnitus. Moreover, melatonin may have properties pro-
tective against ototoxic drugs such as amikacin, gentamicin, or cancer
therapeutic agents that are dose dependent. In vitro, melatonin has
demonstrated antioxidative properties and it has been postulated that
these antioxidative properties contribute to the alleviation of tinnitus.
Melatonin levels used to obtain these findings in vitro, however, are
at supraphysiologic levels; therefore, it is more likely that the benefits
from taking supplemental melatonin occur from minimal antioxidative
properties, sleep enhancement, or other potential methods of action that
are not yet understood. Melatonin offers minimal risk of toxicity with
modest daily doses such as1 to 3 mg, as well as a low cost and favorable
adverse effect profile for older adults. In addition to potential benefits
in the treatment of tinnitus, melatonin also may have beneficial neu-
rogenerative properties. We recommend that melatonin be considered
for use in patients with significant tinnitus.
Key Words: antioxidant, melatonin, tinnitus
Presbycusis (hearing loss) is the most common sensory def-
icit in older adults
1
and can impair communication, leading
to social isolation, loss of independence, depression, anxiety,
cognitive decline, and loneliness.
1,2
Since 2008, tinnitus has
been the most common service-connected disability in military
veterans, according to the Veterans Benefits Administration,
3
and is often caused by exposure to noise. Although tinnitus
can occur anywhere along the auditory pathway, the majority of
occurrences are the result of damage to the cochlea or cochlear
nerve.
4
This damage results in decreased neural input to the brain
with a compensatory hyperstimulation of central auditory
circuits producing the phantom sounds of tinnitus.
5
In a cross-
sectional survey, many Americans reported experiencing tin-
nitus at some point, with 14.3% of those surveyed reporting
frequent tinnitus.
6
Because it is not yet within the reach of
medicine to remedy presbycusis, the optimal management of
comorbid conditions such as tinnitus has the potential to im-
prove quality of life.
The production of free radicals appears linked to ototox-
icity,
2,7
and there is a belief that the use of antioxidants may
result in improved plasma levels of radical scavengers and may
play a role in maintaining hearing and reducing tinnitus.
8
Melatonin is an antioxidant that has emerged not only as a sleep
aid but also as an option in several neurodegenerative disor-
ders.
9
In this review, we explore the role of melatonin in the
management of tinnitus.
Methods
A literature review was conducted in MEDLINE for the
period June 30, 1973YApril 30, 2013. Approximately 250
publications containing ‘‘tinnitus’’ in the title that also combined
‘‘acoustic’’ or ‘‘hearing loss’’ or ‘‘melatonin’’ were reviewed
initially to determine relevance. Approximately 50 articles
were selected for inclusion in this study.
The pineal gland, previously referred to as the ‘‘third eye’’
for its ability to transduce light, is located midline at the roof
Key Points
&Melatonin typically is used in sleep medication.
&Melatonin has antioxidative properties.
&Melatonin may alleviate subjective symptoms of tinnitus.
&Melatonin may have special benefits in combating the oto-
toxicity of aminoglycosides and cancer therapeutic agents.
&Future studies to verify the effectiveness of melatonin in
auditory dysfunction are needed.
Review Article
Southern Medical Journal &Volume 107, Number 6, June 2014 1
From the Sycamore Shoals Hospital, Elizabethton, the Department of Internal
Medicine, Division of Infectious Diseases, and the James H. Quillen
College of Medicine, East Tennessee State University, and the Department
of Medicine, Mountain Home Veterans Affairs Medical Center, Johnson
City, Tennessee.
Reprint requests to Dr Alan N. Peiris, College of Medicine, East Tennessee
State University, PO Box 70622, Bldg 1, Dogwood Ave, Johnson City, TN
37614. E-mail: peiris@etsu.edu; or to Dr Dima Youssef, Department of
Internal Medicine, Division of Infectious Diseases, East Tennessee State
University, PO Box 70622, VAMC Bldg 1, Dogwood Ave, Johnson City,
TN 37614. E-mail: estecina@hotmail.com, youssef@etsu.edu
This material is the result of work supported with resources and the use of
facilities at the Mountain Home Veterans Affairs Medical Center. The
contents of this article do not reflect the position of the US government or
the Department of Veterans Affairs.
The authors have no financial relationships to disclose and no conflicts of
interest to report.
Accepted January 6, 2014
Copyright *2014 by The Southern Medical Association
0038-4348/0Y2000/107-00
DOI: 10.1097/SMJ.0000000000000119
Copyright @ 2014 by The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
of the third ventricle of the brain and is part of the dienceph-
alon. As a person ages, the pineal gland calcifies and is visible
on x-ray. The primary functions of the gland include the syn-
thesis and secretion of melatonin.
Melatonin is a hormone derived from tryptophan, and its
production peaks in humans at ages 1 to 3 years. After this
point, secretion declines steadily and by the time an individual
reaches age 70, he or she may produce only one-fourth of the
amount of melatonin he or she produced as a young adult.
10
Melatonin secretion had a tendency to follow a circadian
rhythm; nocturnal plasma levels are at least 10-fold higher than
diurnal concentrations.
11
As such, melatonin is widely believed
to help with the initiation and maintenance of sleep. Melatonin
also functions as an antioxidant by direct free radical scav-
enging, stimulating mitochondrial antioxidative enzymes, and
augmenting the efficacy of other antioxidants.
12
New possi-
bilities for the role of melatonin, including vasodilatory ef-
fects by sympathetic tone modulation, immunity enhancement
emerging in the literature, and hypertonicity attenuation via
dopamine antagonism orally or intravenously.
13
Melatonin has
the ability to cross the bloodYbrain barrier, thereby allowing
administration via the oral or the intravenous route. This ability,
coupled with low toxicity, makes the hormone appealing for
use in the clinical setting.
10,14
Discussion
Melatonin and Tinnitus
Tinnitus increases with age, peaking between 60 and
69 years of age
6
; affects approximately 50 million people
11
;
and commonly causes general discomfort, fatigue, and sleep
disturbances. Approximately one-fourth of people who experi-
ence tinnitus report that their symptoms increase in severity
over time.
15
Despite the large number of individuals affected by tin-
nitus, no drugs for its treatment have been approved by the
US Food and Drug Administration.
16
Common treatments for
tinnitus include cognitive-behavioral therapy (CBT), relaxa-
tion training, and mindfulness-based techniques. Face-to-face
CBT treatments have a greater effect in improving tinnitus-
related distress, anxiety, and depression
17,18
than Internet-
based CBT interventions.
18
CBT, however, is not effective
in reducing the disturbance caused by tinnitus noise level.
19
Tinnitus-specific CBT treatment strategies include psycho-
education, management of avoidance, sleep hygiene, relaxa-
tion training, and coping strategies. Surgical techniques have
proven successful in some cases, although these surgical op-
tions do not provide a valid and reliable mode of treatment
for subjective tinnitus.
20
Translabyrinthine procedures for the
removal of acoustic neuromas and sectioning of the eighth
cranial nerve may yield only a 40% reported improvement in
tinnitus. Middle cranial fossa section of the vestibular nerve
may cause tinnitus to remain the same or worsen. Stapedec-
tomy improves tinnitus in only 50% of cases.
20
Cochlear implant can improve tinnitus with use of the
stimulator and implant.
20
Other treatment options include
classical neuromodulation techniques such as vagus nerve
stimulation paired with tones excluding the tinnitus-matched
frequency, which alleviates the perceived sound and distress
in patients who are not taking medication.
21
Plasma melatonin levels have been found to be lower in
patients with subjective idiopathic tinnitus compared with those
in their respective age group who do not experience tinnitus.
22
Patients with tinnitus who were given 3 mg/day of melatonin
demonstrated improved scores on both the Tinnitus Handicap
Inventory (THI) and the Pittsburgh Sleep Quality Index (PSQI).
The effectiveness of melatonin as measured by the THI was
not associated with the severity of tinnitus in this study; however,
its effectiveness in sleep increased in individuals reporting the
poorest sleep quality at the onset of the study.
23
Megwalu et al
concluded that improvements in tinnitus were the result of
the effects of melatonin on sleep and that melatonin is an
effective intervention in patients, regardless of the severity
of their tinnitus symptoms.
23
Melatonin, administered in combination with sulodexide,
an antithrombotic heparin molecule that improves blood flow
in microcirculation, has been shown to be more effective in
relieving subjective symptoms associated with tinnitus. In one
study, 3 mg of melatonin given alone and in combination
with 250 mg of sulodexide was more effective in improving
symptoms of tinnitus, with the combination being the most
effective dosage.
24
Three mg of melatonin was the most common dose ad-
ministered in the clinical trials reviewed in this article. At this
strength, the use of melatonin resulted in improvement in people
with subjective complaints of tinnitus.
23,25Y27
and participants
slept better while taking the hormone regimen.
23
The individuals
who received the most benefit from the effects of melatonin
effects were men who did not have a history of depression, had
not received previous treatment for tinnitus and had a history
of noise exposure.
28
Further research should be conducted to
determine the optimal dose of melatonin required to achieve
maximal benefits in tinnitus management. At this time, a 3-mg
dose appears to be ideal, is well tolerated in subjects, and has
been shown to achieve partial relief of subjective tinnitus.
Melatonin and Ototoxic Drugs
Melatonin shows promise for protection against ototoxic
drugs, specifically aminoglycosides and cancer agents. In
humans, it has been shown to be 150 times more effective in
limiting cochlear adverse effects versus a mixture of antioxidants
consisting of glutathione, ascorbate, tocopherol, and N-acetyl-
cysteine.
28
A study in rats found that melatonin also protected
hearing from ototoxicity produced by aminoglycosides. Genta-
micin was injected intramuscularly at 160 mg/kg body weight per
day for 5 days and tobramycin was injected intramuscularly at
200 mg/kg body weight per day for 5 days. Melatonin was
administered in three ways: 10 mg/L was placed in their daily
Merrick et al &Does Melatonin Have Therapeutic Use in Tinnitus?
2*2014 Southern Medical Association
Copyright @ 2014 by The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
drinking water from 1 week before the experiment to the end of
the experimental period; 250 mg was given subcutaneously
daily; and 250 mg was injected intramuscularly daily. Melatonin
did not interfere with the antibiotic capacity of the drugs.
7
Injecting rats with melatonin or placing it in their drinking water
significantly reduced the length of the rats’ recovery period in
experiencing ototoxicity from gentamicin.
7
A trial in guinea
pigs found that melatonin protected against the ototoxic effects
of gentamicin.
29
Melatonin protected against ototoxicity with amikacin
30
and does appear to have dose-related effects. Rats receiving
a low dose of 0.4 mg/kg of melatonin were protected from
amikacin-induced ototoxicity, whereas those that received a
high dose of 4 mg/kg of melatonin experienced the ototoxic
effects of the drug.
30
Toxicity could have resulted from the
vasodilator effect of high-dose melatonin because the protec-
tive antioxidative effect occurs with lower doses of melatonin.
Because of this possibility and minimal availability of human
research, providers should exercise caution when prescribing
ototoxic drugs to patients taking large doses of melatonin
and should monitor patients closely for ototoxic potentiation
resulting from any combination of these agents.
Short-term melatonin use of up to 3 months is likely safe
for the majority of adults
31
; however, it may cause headache,
nausea, short-term feelings of depression, daytime sleepiness,
dizziness, stomach cramps, irritability, and low body temper-
ature. In addition, melatonin can interact with some medications,
such as anticoagulants, immunosuppressants, oral contracep-
tives, and hypoglycemic agent medications. Melatonin also
may worsen symptoms of orthostatic hypotension and may
exacerbate Parkinsonian symptoms and neurodegeneration in
Parkinson disease.
32
Melatonin as an Antioxidant
Available research acknowledges melatonin as an anti-
oxidant; however, an unanswered question is whether mela-
tonin is an effective antioxidant at concentrations seen in vivo
because research on this aspect is scant. To obtain antioxidative
effects in vitro, supraphysiologic levels (as much as 100,000
times that which is found in vivo), are required.
33
Although
melatonin has low toxicity, its receptors are highly susceptible
to desensitization.
34,35
Large doses of melatonin tend to be well
tolerated in patients; conversely, the supraphysiologic levels
required for a measurable in vitro antioxidative effect have a
Table. Clinical trial results
Ref no. Study type No. participants Objective Outcomes
Human studies
8 Cross-sectional 126 Is there a relation between plasma
melatonin levels and hearing loss?
Lower plasma levels of melatonin were
found in subjects with hearing loss
22 Prospective 139 Determine association of tinnitus with
plasma levels of melatonin,
vitamin C, and vitamin B
12
Plasma levels of melatonin and B
12
were
lower in subjects with tinnitus
23 Prospective, open-label study 24 Determine whether melatonin has
potential to improve tinnitus,
thereby improving sleep
Use of 3 mg/d melatonin for 4 wk
demonstrated improvement in tinnitus
and sleep
24 Prospective, randomized
clinical trial
102 Does a combination of melatonin
and sulodexide alleviate tinnitus?
Melatonin and sulodexide affect
tinnitus positively
25 Prospective, randomized,
double-blind, crossover
clinical trial
61 Does oral melatonin effectively
treat tinnitus?
Statistically significant decrease
(PG0.05) in tinnitus and an
improvement in sleep
26 Prospective, randomized,
double-blind, placebo-controlled,
crossover trial
30 Determine whether melatonin provides
effective treatment of tinnitus
Melatonin proved to be an effective
treatment for subjective tinnitus
27 Prospective, randomized,
double-blind, placebo-controlled
study
125 Does a combination of sulpiride and
melatonin decrease tinnitus?
Proven to be an effective treatment while
decreasing dopamine activity
Animal studies
7 Laboratory/animal study Reduction of ototoxic effects of
cisplatinum with administration
of melatonin and antioxidants
Melatonin coupled with antioxidants
shortened recovery period from
ototoxic effects of cisplantin
29 Laboratory/animal study Does melatonin reduce gentamicin
ototoxicity?
Melatonin significantly decreased presbycusis
caused by gentamicin (PG0.01)
30 Laboratory/animal study Does melatonin have a dose-dependent
benefit on aminoglycoside ototoxicity?
Low-dose melatonin provided protection,
whereas high-dose melatonin enhanced
ototoxic effects
Review Article
Southern Medical Journal &Volume 107, Number 6, June 2014 3
Copyright @ 2014 by The Southern Medical Association. Unauthorized reproduction of this article is prohibited.
paradoxical effect and lead to sleep impairment caused by the
tolerance of melatonin receptors.
35
Commonlymarketed strengths for melatonin are 1 to 10 mg,
which can raise plasma concentrations 3 to 60 times above
normal peak values.
36
Several studies have found that doses as
low as0.1 to 0.3 mg of melatonin approximate physiologic levels,
whereas any higher dosage causes a supraphysiologic state
in a pharmacokinetically linear fashion.
37
In most clinical trials,
3 mg of melatonin was the dose used to determine whether it
is an effective treatment for tinnitus. Studies confirm, however,
that subjective complaint of tinnitus and difficulties with sleep
are reduced considerably by the administration of 3 mg of
melatonin. A wide range of doses was used and the doses were
administered for up to 4 weeks. The trials that examined the
efficacy of melatonin in people with primary sleep disorders
were of relatively short duration (e4 weeks) as were the
trials examining the safety of melatonin in the same population
(e3months).
38
Megwalu et al showed that the mean THI score
decreased significantly between weeks 0 and 4 and between
weeks 0 and 8. The mean PSQI significantly decreased between
weeks 0 and 4 and between weeks 0 and 8. The change in PSQI
was significantly associated with the change in THI between
weeks 0 and 4.
23
Rosenberg et al
26
evaluated a nightly supplement of 3 mg
melatonin for 30 days preceded by or followed by a nightly
placebo for 30 days with a 7-day washout period between
medications. This study showed that the average pretreatment
THI score for patients who reported overall improvement with
melatonin was statistically higher than the score for patients
who reported no improvement with melatonin. Difficulty in
sleeping attributable to tinnitus improved in 46.7% of patients/
individuals after melatonin compared with 20.0% taking a
placebo.
26
This demonstrates that either only a minimal amount
of the antioxidative effect of melatonin is sufficient to help re-
duce subjective tinnitus or the improvement in sleep accounts
for the primary benefit. Perhaps melatonin has another method
of action which has not been elucidated.
Other theories of how melatonin may decrease tinnitus
include a modulatory effect on the central nervous system. This
results in reduced sympathetic drive, allowing for enhancement
of labyrinthine perfusion; the relaxation of the tensor tympani
muscle, which could relieve tinnitus of muscular origin and
exert an antidepressive effect; and immunomodulation.
13
Although clinical trials are lacking in animal studies, mel-
atonin has been found to protect against the histological changes
seen in Alzheimer disease.
39
Olcese et al recommended long-
term melatonin therapy as a primary or complementary strategy
for abating the progression of Alzheimer disease. Secondary
strategies may include anti-amyloid-beta aggregation and
melatonin’s anti-inflammatory and/or antioxidative properties.
This recommendation was based on their study of the potential
for long-term melatonin treatment to protect Alzheimer-
transgenic mice against cognitive impairment and develop-
ment of amyloid-betaYbased neuropathology. In the study,
100 mg of melatonin per liter of drinking water was given to
APP + PS1 double transgenic mice from 2 to 2.5 monthsof age to
their death at age 7.5 months. A comprehensive behavioral
battery administered during the final 6 weeks of treatment re-
vealed that transgenic mice given melatonin were protected
against cognitive impairment, whereas transgenic control mice
remained impaired.
40
The T1Table summarizes and compares the
different clinical trials included in this study.
Other potential research areas for the use of melatonin in
the treatment of neurodegenerative disorders include Parkinson
disease, amyotrophic lateral sclerosis, and traumatic brain in-
jury, but they would be secondary to the drug’s antioxidant and
sleep effects.
39
A vast number of other agents such as >-lipoic
acid, coenzyme Q10, resveratrol, vitamin C, folate, and vitamin
B
12
have been used and may have some benefit in the man-
agement of tinnitus.
2,41
We do not know, however, whether the
addition of these agents to melatonin therapy has synergy in
terms of improving tinnitus.
Conclusions
Melatonin has been shown to help alleviate tinnitus and
associated symptoms such as sleep difficulties. Whether mela-
tonin produces this desired effect through antioxidative proper-
ties, neurodegenerative properties, immunomodulation, vascular
perfusion, or simply its effect on sleep warrants further re-
search via randomized controlled trials. Because of the relative
safety of melatonin and positive outcomes from clinical trials,
considering melatonin treatment in patients with tinnitus is
reasonable. In addition to tinnitus therapy, melatonin may dem-
onstrate special benefits in combating the ototoxicity of amino-
glycosides and cancer therapeutic agents.
22
It is important to
note that low doses of melatonin protected rodent ears from
ototoxicity, but a high dose facilitated amikacin-induced oto-
toxicity; therefore, using the minimum effective dose of mela-
tonin and lower doses such as 1 mg/day are recommended
pending further research to determine the optimal dose.
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Review Article
Southern Medical Journal &Volume 107, Number 6, June 2014 5
