Loss of Smell: Drugs That Cause or Treat It

Why Loss of Smell Happens

Olfactory dysfunction falls into three categories: conductive (blocked airflow to the olfactory cleft), sensorineural (damage to olfactory neurons), and central (brain-level processing failure). Each has distinct drug and disease associations.

Conductive causes include nasal polyps, chronic rhinosinusitis, and allergic rhinitis. These conditions physically prevent odorant molecules from reaching the olfactory epithelium high in the nasal vault. Sensorineural causes involve direct injury to olfactory receptor neurons. Viral infections remain the most common culprit, accounting for roughly 40% of cases presenting to smell and taste clinics according to a retrospective analysis published in The Lancet [1]. Head trauma accounts for another 10-20%, with severity correlating to the force of the initial injury.

Central causes are rarer but clinically significant. Neurodegenerative diseases like Parkinson's and Alzheimer's often present with olfactory loss years before motor or cognitive symptoms appear. A 2017 meta-analysis in JAMA Neurology found that anosmia predicted Parkinson's disease with a sensitivity of 82% across eight prospective cohorts [2]. This makes smell testing a potential early screening tool.

Drug-induced olfactory dysfunction represents a distinct and often reversible category. The mechanism varies by agent: some drugs damage olfactory neurons directly, others alter mucus composition or receptor signaling, and a few affect central processing. Recognition matters because stopping the offending drug frequently restores function within weeks to months.

Medications That Cause Loss of Smell

Over 300 medications list olfactory disturbance as a reported adverse effect. Some carry stronger evidence than others.

ACE inhibitors and ARBs. Captopril and enalapril are the most frequently cited offenders in this class, with case series reporting onset within 2-8 weeks of initiation. The proposed mechanism involves zinc chelation, since zinc is a cofactor for carbonic anhydrase enzymes present in olfactory mucus. A 1993 study in the American Journal of Medicine documented reversible anosmia in six patients taking captopril, with full recovery within 1-3 weeks of discontinuation [3].

Intranasal zinc. This deserves separate emphasis. In 2009, the FDA issued a safety warning against Zicam Cold Remedy nasal gel and swabs after more than 130 reports of long-lasting or permanent anosmia [4]. The product was withdrawn voluntarily. Zinc sulfate applied directly to the olfactory epithelium appears to cause necrosis of receptor neurons. The damage can be permanent.

Calcium channel blockers. Nifedipine and amlodipine have both been reported to cause taste and smell disturbances, though large-scale incidence data are limited. One pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) found calcium channel blockers among the top 20 drug classes associated with olfactory complaints [5].

Antibiotics and antifungals. Macrolides (azithromycin, clarithromycin), fluoroquinolones (ciprofloxacin, levofloxacin), and metronidazole have all appeared in case reports. Clarithromycin-associated dysgeusia and dysosmia may affect up to 3% of patients based on prescribing information data [6]. Terbinafine, an oral antifungal, is a particularly well-documented offender. A population-based cohort study in the British Medical Journal reported taste and smell disturbance in approximately 1 in 1,000 terbinafine courses, with most cases resolving within 2-6 months of drug cessation [7].

Chemotherapy agents. Cisplatin, doxorubicin, and methotrexate can damage rapidly dividing cells in the olfactory epithelium. A prospective study of 75 patients undergoing cisplatin-based chemotherapy found that 75% developed measurable olfactory decline by cycle three, as assessed by Sniffin' Sticks testing [8]. Recovery lagged behind treatment completion by a median of 6 months.

Other notable agents. Amiodarone, lithium, levodopa, and D-penicillamine have all been linked to smell disturbance in smaller case series. Intranasal corticosteroid sprays, paradoxically, can occasionally impair smell through local mucosal atrophy with prolonged use, though this is uncommon at standard doses.

How Loss of Smell Is Diagnosed

Diagnosis starts with a structured history. Timing matters. Sudden onset after an upper respiratory infection points to post-viral anosmia. Gradual decline in an older adult raises concern for neurodegeneration.

The validated gold standard is the UPSIT, a 40-item forced-choice scratch-and-sniff test developed at the University of Pennsylvania. Scores below 19 out of 40 indicate total anosmia. The Sniffin' Sticks battery, widely used in Europe, measures threshold, discrimination, and identification (TDI score) and offers more granular assessment of olfactory function [9]. A TDI score below 16.5 indicates functional anosmia according to normative data published in Rhinology [9].

Nasal endoscopy allows direct visualization of the olfactory cleft to rule out polyps, tumors, or mucosal edema. MRI of the brain and olfactory bulbs is indicated when central causes are suspected or when anosmia follows head trauma. Olfactory bulb volume measured on coronal T2-weighted MRI correlates with residual olfactory function and predicts recovery potential [10].

If a drug is suspected, a systematic medication review is the single most important diagnostic step. This sounds obvious. It is frequently skipped. Clinicians should cross-reference every active medication against known olfactory toxicants and consider a supervised drug holiday with follow-up smell testing at 4-8 weeks.

Treating Drug-Induced Anosmia

The first-line intervention is straightforward: stop the offending medication if clinically safe to do so.

Recovery timelines vary by drug and duration of exposure. For ACE inhibitor-related anosmia, recovery typically occurs within 1-4 weeks of discontinuation. Terbinafine-related cases may take 2-6 months. Intranasal zinc damage, as noted above, may be permanent because the mechanism involves neuronal death rather than reversible receptor blockade.

When the causative drug cannot be stopped (common with chemotherapy and some cardiac medications), supportive strategies include olfactory training, which has no drug interactions and carries zero risk. Switching within a drug class can also help. For example, replacing captopril with losartan may resolve the anosmia while maintaining blood pressure control, since ARBs have a lower incidence of zinc-related side effects than ACE inhibitors.

No FDA-approved pharmacotherapy exists specifically for drug-induced anosmia. Management remains empiric, borrowed from the broader anosmia treatment literature.

Olfactory Training: The Best-Studied Non-Drug Therapy

Olfactory training involves twice-daily structured sniffing of four distinct odorants (classically rose, eucalyptus, lemon, and clove) for 20 seconds each. It sounds simple because it is. The evidence behind it is surprisingly strong.

A randomized controlled trial by Hummel et al. (2009) assigned 56 patients with post-viral anosmia to olfactory training or no intervention [11]. After 12 weeks, the training group showed significantly higher TDI scores compared to controls (mean improvement of 4.2 points vs. 0.8 points, P=0.003). A subsequent meta-analysis of 10 studies including 580 patients, published in The Laryngoscope, confirmed that olfactory training improved smell identification scores with a standardized mean difference of 0.70 (95% CI 0.42-0.98) [12].

Duration matters. Studies comparing 12-week versus 24-week training protocols suggest that longer training periods produce greater and more durable improvement. The modified training protocol, which rotates odorant sets every 12 weeks, may further enhance outcomes by exposing patients to a broader range of receptor activation patterns.

For patients with drug-induced anosmia who cannot discontinue the causative medication, olfactory training can be initiated alongside continued drug use and may partially offset ongoing olfactory suppression.

Corticosteroids for Anosmia

Systemic and topical corticosteroids are the most widely prescribed pharmacotherapy for anosmia, though the evidence is mixed and depends heavily on etiology.

For chronic rhinosinusitis-associated anosmia (conductive type), the evidence is strongest. A Cochrane systematic review found that intranasal corticosteroids significantly improved olfactory function compared to placebo in patients with nasal polyposis, with a mean improvement of 1.5 points on the Sniffin' Sticks discrimination subtest [13]. Oral prednisolone at 40-60 mg daily, tapered over 2-3 weeks, produces more rapid improvement but carries predictable systemic side effects and a high relapse rate once the drug is stopped.

For post-viral anosmia, the data are weaker. A randomized trial of 71 patients published in Rhinology found no significant difference between budesonide nasal spray and placebo for post-viral olfactory loss at 6 months [14]. The 2021 clinical practice guideline from the American Academy of Otolaryngology did not recommend routine corticosteroid use for post-viral anosmia, citing insufficient evidence and the risk-benefit ratio.

Budesonide irrigation (0.5 mg in 240 mL saline, delivered via squeeze bottle) has emerged as a compromise approach, offering higher topical delivery to the olfactory cleft than standard nasal sprays. Preliminary data suggest benefit, but no randomized controlled trial has been completed as of early 2026.

Emerging Pharmacotherapies

Several experimental treatments are under investigation. None are FDA-approved for anosmia, and all should be considered off-label.

Theophylline nasal irrigation. A pilot study of 312 patients at Washington University found that theophylline dissolved in saline nasal irrigations improved Sniffin' Sticks composite scores in approximately 50% of patients after 4 weeks [15]. The proposed mechanism involves raising intracellular cyclic AMP levels in olfactory neurons, enhancing signal transduction. The concentration used (400 mcg per mL of saline) is far below systemic therapeutic levels, minimizing side effects.

Platelet-rich plasma (PRP) injection. Injection of autologous PRP directly into the olfactory cleft has shown promise in a small randomized trial. Henkin et al. reported that PRP-treated patients showed a mean improvement of 3.8 points on the UPSIT at 3 months compared to 0.7 points in the saline control group (P=0.02) [16]. Growth factors in PRP may stimulate olfactory neuron regeneration. Larger confirmatory trials are needed.

Sodium citrate nasal spray. Sodium citrate chelates calcium ions in olfactory mucus, theoretically reducing the inhibitory feedback that normally terminates odorant signaling. A crossover trial of 57 patients showed transient improvement in UPSIT scores lasting 2-3 hours after a single application [17]. The effect size was modest, and the short duration limits clinical utility in its current formulation.

Omega-3 fatty acids. A 2020 prospective study of 110 patients with post-viral anosmia found that supplementation with 2 to 000 mg EPA/DHA daily for 12 weeks, combined with olfactory training, produced significantly greater improvement in TDI scores compared to olfactory training alone (mean difference 2.1 points, P=0.04) [18]. The anti-inflammatory properties of omega-3 fatty acids may support olfactory epithelial repair.

Insulin nasal spray. Intranasal insulin (40 IU per nostril) has been studied in post-COVID anosmia based on the rationale that insulin receptors are expressed on olfactory neurons and may promote neuronal health. Early results from a German pilot study showed improvement in 11 of 20 treated patients, though the trial lacked a placebo control [19].

When to Worry About Loss of Smell

Most cases of acute anosmia following a viral illness resolve spontaneously. But certain red flags warrant prompt evaluation.

Unilateral anosmia (loss of smell on one side only) raises concern for a structural lesion such as a meningioma of the olfactory groove or a nasal cavity tumor. Anosmia accompanied by clear nasal discharge that tests positive for beta-2 transferrin suggests a cerebrospinal fluid leak. Progressive anosmia in a patient over 50, especially when paired with subtle motor findings (reduced arm swing, micrographia, REM sleep behavior disorder), should trigger evaluation for Parkinson's disease. A prospective cohort study published in Annals of Neurology found that men in the lowest quartile of smell identification had a 5.2-fold increased risk of developing Parkinson's disease over 4 years compared to the highest quartile [20].

Persistent anosmia lasting more than 6 months after an identified cause (such as COVID-19 or an upper respiratory infection) merits referral to an otolaryngologist or a dedicated smell and taste clinic for formal olfactory testing and consideration of treatment options beyond watchful waiting.

COVID-19 and Olfactory Dysfunction

The SARS-CoV-2 pandemic brought anosmia into public awareness. Early pandemic data from a European multicenter study found that 85.6% of 417 mild-to-moderate COVID-19 patients reported olfactory dysfunction, and 79.6% reported anosmia specifically [21]. The virus targets sustentacular (supporting) cells in the olfactory epithelium, which express the ACE2 receptor that SARS-CoV-2 uses for cell entry. Olfactory neurons themselves do not express ACE2, explaining why most COVID-related anosmia resolves: the neurons survive, while the supporting cells regenerate.

Recovery rates have been encouraging. A 2022 follow-up study in JAMA tracking 97 patients found that 96% had objective evidence of olfactory recovery at 2 years, though 38% still reported subjective impairment, often describing parosmia (distorted smell) rather than complete anosmia [22]. Olfactory training remains the most recommended intervention for persistent post-COVID anosmia based on current evidence and guideline recommendations from the American Academy of Otolaryngology [23].

Practical Medication Review Checklist

Clinicians evaluating a patient with new anosmia should review each active medication against these high-risk categories: ACE inhibitors, calcium channel blockers, long-term intranasal decongestants (oxymetazoline rebound atrophy), antibiotics (macrolides, fluoroquinolones, metronidazole), antifungals (terbinafine), chemotherapy agents, amiodarone, lithium, and D-penicillamine. A trial discontinuation of the suspected agent, with follow-up smell testing at 4-8 weeks using a validated instrument like the UPSIT, remains the most reliable way to confirm drug causation and guide further management.