Antimalarials and tinnitus: quinine, chloroquine, mefloquine

Antimalarial drugs in the quinoline chemical family have been associated with tinnitus and hearing loss since the nineteenth century, when quinine was the primary treatment for malaria worldwide. Despite the introduction of newer agents, quinoline-based antimalarials remain in clinical use for prevention and treatment of malaria in travelers, as well as for certain autoimmune conditions. Their capacity to affect the inner ear is well established, and patients receiving these drugs should understand the risk.

How quinoline antimalarials affect the inner ear

The precise mechanism by which quinoline compounds produce ototoxicity is not fully resolved, but several pathways have been proposed. Quinine appears to inhibit prestin, the motor protein in outer hair cells that drives electromotility and cochlear amplification. This reduces the ear’s ability to amplify soft sounds and can generate the phantom noise of tinnitus.

Chloroquine and hydroxychloroquine may act partly through mitochondrial dysfunction and oxidative stress in cochlear tissue. Animal studies have shown drug accumulation in melanin-containing structures of the inner ear, including the stria vascularis and spiral ligament, where the compounds can persist long after dosing ends.

Mefloquine, a structurally related but distinct agent, primarily targets neurological tissues and has both auditory and vestibular effects. Its side-effect profile prompted the FDA to add a black-box warning in 2013 noting that neurological and psychiatric adverse effects, including tinnitus, can persist after the drug is stopped.

Quinine

Quinine remains in clinical use as a second-line treatment for severe malaria in parts of the world where resistance to other agents is high. In past decades it was widely prescribed for nocturnal leg cramps, but most major medical bodies, including NHS UK, have moved away from this indication because the risk-benefit ratio is unfavorable for a non-life-threatening condition.

At therapeutic doses for malaria treatment, tinnitus is one of the most commonly reported side effects. It typically appears within the first few days of a course and is dose-dependent. The package of symptoms that includes tinnitus, headache, nausea, and visual disturbance is called cinchonism. At standard doses, tinnitus from quinine is generally considered reversible once the drug is discontinued.

High-dose or long-term quinine exposure carries a greater risk of permanent cochlear damage, which is why careful dosing, especially in patients with renal impairment (which slows drug clearance), is important.

Chloroquine and hydroxychloroquine

Chloroquine was once the first-line treatment for malaria globally, but widespread parasite resistance has reduced its utility for that indication in many regions. It remains prescribed for malaria prophylaxis where the parasite population is still sensitive. Hydroxychloroquine, a hydroxylated derivative with a generally milder adverse-effect profile, is used long-term for systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune conditions.

Both compounds have documented ototoxic potential. The risk with hydroxychloroquine at standard rheumatologic doses is lower than with chloroquine but not negligible over years of use. The American College of Rheumatology guidelines for hydroxychloroquine monitoring focus primarily on retinal toxicity screening, but audiological monitoring is part of the broader safety picture for long-term users.

Cochlear accumulation of these compounds is a key concern. Because they bind to melanin, they can concentrate in pigmented cochlear structures and remain present for months after stopping the drug. This means that hearing changes can potentially appear or continue after a course ends.

Mefloquine

Mefloquine is used for prophylaxis in travelers to regions with chloroquine-resistant malaria, as well as for treatment in some contexts. It is taken weekly rather than daily for prophylaxis, which simplifies adherence but means the drug accumulates over longer periods.

Tinnitus and dizziness are among the recognized auditory and vestibular adverse effects. The 2013 FDA black-box warning drew attention to the possibility that neurological and psychiatric effects, including tinnitus and dizziness, can occasionally become permanent. The warning does not preclude use in appropriate patients but requires that prescribers discuss these risks explicitly before starting treatment.

Travelers should report any new tinnitus, hearing change, or dizziness to a clinician promptly during a mefloquine course. Switching to an alternative agent (such as doxycycline or atovaquone-proguanil) may be possible if mefloquine-related symptoms appear and the travel itinerary permits.

Who is most at risk

Several factors increase susceptibility to ototoxic effects from antimalarials:

• Pre-existing cochlear damage from noise exposure or aging
• Renal impairment, which slows drug clearance and raises plasma concentrations
• High doses or prolonged treatment duration
• Concurrent use of other ototoxic agents, such as aminoglycoside antibiotics or loop diuretics
• Possible genetic variants affecting drug metabolism or cochlear transport

Children are considered especially vulnerable because any hearing loss has long-lasting effects on language development and educational attainment. Pediatric dosing regimens for quinoline antimalarials require careful weight-based calculation.

Symptoms to report

Patients taking any quinoline antimalarial should seek prompt medical attention if they notice:

• New ringing, buzzing, or hissing in one or both ears
• Sudden reduction in hearing clarity
• Dizziness or balance disturbance
• Ear fullness that was not previously present

Reporting symptoms early, while the drug is still being taken, allows the prescriber to assess whether dose reduction, drug change, or audiological evaluation is warranted.

Practical context for travelers

Most people taking short-course prophylaxis for a two- or three-week trip do not develop lasting ototoxicity. The concern is proportionally greater with longer courses and higher-dose treatment regimens. Travelers should ensure the prescribing clinician is aware of any existing hearing condition or tinnitus before a quinoline antimalarial is selected.

In many travel contexts, equally effective alternatives with lower ototoxic potential exist and can be prescribed instead. Atovaquone-proguanil (Malarone) and doxycycline are not associated with the same quinoline-class ototoxic effects and are appropriate first choices for many travel itineraries.

If symptoms persist or change, see an audiologist or physician.